Imaging using near-infrared laser diodes with distributed bragg reflectors

ABSTRACT

A smart phone or tablet includes a first part having at least one laser diode configured to be pulsed, and a second part having at least one other laser diode, the laser diodes configured to generate near-infrared light, wherein at least some of the laser diodes comprise a distributed Bragg reflector, with some laser diode light directed to tissue including skin. An array of laser diodes generates near-infrared light and includes one or more distributed Bragg reflectors. An assembly in front of the array to forms light spots on the tissue. A first receiver includes detectors that receive light reflected from the tissue. An infrared camera generates data from light reflected from the tissue. The smart phone or tablet generates a two-dimensional or three-dimensional image or mapping using the infrared camera data, and includes a wireless receiver, a wireless transmitter, a display, a voice input module, and a speaker.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/015,737 filedJun. 22, 2018, which is a continuation of U.S. Ser. No. 15/594,053 filedMay 12, 2017, which is a continuation of U.S. application Ser. No.14/875,709 filed Oct. 6, 2015, now U.S. Pat. No. 9,651,533 issued May16, 2017, which is a continuation of U.S. application Ser. No.14/108,986 filed Dec. 17, 2013, now U.S. Pat. No. 9,164,032 issued Oct.20, 2015, which claims the benefit of U.S. provisional application Ser.No. 61/747,487 filed Dec. 31, 2012, the disclosures of which are herebyincorporated in their entirety by reference herein.

This application is related to U.S. provisional applications Ser. Nos.61/747,477 filed Dec. 31, 2012; Ser. No. 61/747,481 filed Dec. 31, 2012;Ser. No. 61/747,485 filed Dec. 31, 2012; Ser. No. 61/747,472 filed Dec.31, 2012; Ser. No. 61/747,492 filed Dec. 31, 2012; Ser. No. 61/747,553filed Dec. 31, 2012; and Ser. No. 61/754,698 filed Jan. 21, 2013, thedisclosures of which are hereby incorporated in their entirety byreference herein.

This application is also related to International Application No.PCT/US2013/075700 (Publication No. WO/2014/105520) entitledNear-Infrared Lasers For Non-Invasive Monitoring Of Glucose, Ketones,HBA1C, And Other Blood Constituents; International ApplicationPCT/US2013/075736 (Publication No. WO/2014/105521) entitled Short-WaveInfrared Super-Continuum Lasers For Early Detection Of Dental Caries;U.S. application Ser. No. 14/108,995 (Publication No. 2014/0188092)entitled Focused Near-Infrared Lasers For Non-Invasive Vasectomy AndOther Thermal Coagulation Or Occlusion Procedures; InternationalApplication PCT/US2013/075767 (Publication No. WO/2014/143276) entitledShort-Wave Infrared Super-Continuum Lasers For Natural Gas LeakDetection, Exploration, And Other Active Remote Sensing Applications;U.S. application Ser. No. 14/108,974 (Publication No. 2014/0188094)entitled Non-Invasive Treatment Of Varicose Veins; and U.S. applicationSer. No. 14/109,007 (Publication No. 2014/0236021) entitledNear-Infrared Super-Continuum Lasers For Early Detection Of Breast AndOther Cancers, the disclosures of which are hereby incorporated in theirentirety by reference herein.

BACKGROUND AND SUMMARY

Counterfeiting of pharmaceuticals is a significant issue in thehealthcare community as well as for the pharmaceutical industryworldwide. For example, according to the World Health Organization, in2006 the market for counterfeit drugs worldwide was estimated at around$43 Billion. Moreover, the use of counterfeit medicines may result intreatment failure or even death. For instance, in 1995 dozens ofchildren in Haiti and Nigeria died after taking counterfeit medicinalsyrups that contained diethylene glycol, an industrial solvent. Asanother example, in Asia one report estimated that 90% of Viagra sold inShanghai, China, was counterfeit. With more pharmaceuticals beingpurchased through the internet, the problem of counterfeit drugs comingfrom across the borders into the United States has been growing rapidly.

A rapid, non-destructive, non-contact optical method for screening oridentification of counterfeit pharmaceuticals is needed. Spectroscopyusing near-infrared or short-wave infrared (SWIR) light may provide sucha method, because most pharmaceuticals comprise organic compounds thathave overtone or combination absorption bands in this wavelength range(e.g., between approximately 1-2.5 microns). Moreover, most drugpackaging materials are at least partially transparent in thenear-infrared or SWIR, so that drug compositions may be detected andidentified through the packaging non-destructively. Also, using anear-infrared or SWIR light source with a spatially coherent beampermits screening at stand-off or remote distances. Beyond identifyingcounterfeit drugs, the near-infrared or SWIR spectroscopy may have manyother beneficial applications. For example, spectroscopy may be used forrapid screening of illicit drugs or to implement process analyticaltechnology in pharmaceutical manufacturing. There are also a wide arrayof applications in assessment of quality in the food industry, includingscreening of fruit, vegetables, grains and meats.

In one embodiment a measurement system includes a light sourceconfigured to generate an output optical beam. The light source includesa plurality of semiconductor sources configured to generate an inputoptical beam, a multiplexer configured to receive at least a portion ofthe input optical beam and to form an intermediate optical beam, one ormore fibers configured to receive at least a portion of the intermediateoptical beam and to form the output optical beam wherein at least aportion of the one or more fibers comprises a fused silica fiber,wherein the output optical beam comprises one or more opticalwavelengths, and wherein the output optical beam is modulated at amodulation frequency. The system includes a light beam set-up comprisinga monochromator configured to receive at least a portion of the outputoptical beam and to form a filtered optical beam, and a measurementapparatus configured to receive a received portion of the filteredoptical beam and to deliver a delivered portion of the filtered opticalbeam to a sample. The measurement system also includes a receiverconfigured to receive at least a portion of a spectroscopy output beamfrom the sample that is generated by the delivered portion of thefiltered optical beam, wherein the receiver is further configured to usea lock-in technique that detects the modulation frequency, and whereinthe receiver is further configured to generate a first signal inresponse to light received while the light source is off, and generate asecond signal in response to light received while the light source ison. The measurement system is configured to improve a signal-to-noiseratio of the spectroscopy output beam by differencing the first signaland the second signal. The receiver is further configured to process theat least a portion of the spectroscopy output beam to generate an outputsignal, wherein the receiver processing includes at least in part usingchemometrics or multivariate analysis to permit identification ofmaterials within the sample. The output signal is based at least in parton a chemical composition of the sample.

In one embodiment, a measurement system includes a light sourceconfigured to generate an output optical beam. The light source includesa plurality of semiconductor sources configured to generate an inputoptical beam, a multiplexer configured to receive at least a portion ofthe input optical beam and to form an intermediate optical beam, and oneor more fibers configured to receive at least a portion of theintermediate optical beam and to form the output optical beam, whereinat least a portion of the one or more fibers comprises a fused silicafiber, wherein the output optical beam comprises one or more opticalwavelengths, and wherein the output optical beam is modulated at amodulation frequency. The system includes a light beam set-up configuredto receive at least a portion of the output optical beam and to form afiltered optical beam, a measurement apparatus configured to receive areceived portion of the filtered optical beam and to deliver a deliveredportion of the filtered optical beam to a sample, and a receiverconfigured to receive at least a portion of a spectroscopy output beamgenerated from the sample by the delivered portion of the filteredoptical beam, wherein the receiver is further configured to use alock-in technique that detects the modulation frequency. The receiver isfurther configured to generate a first signal in response to lightreceived while the light source is off and generate a second signal inresponse to light received while the light source is on. The measurementsystem is configured to improve a signal-to-noise ratio of thespectroscopy output beam by differencing the first signal and the secondsignal. The receiver is further configured to process the at least aportion of the spectroscopy output beam to generate an output signal,and the light source and the receiver are remote from the sample.

In one embodiment, a measurement system includes a light sourceconfigured to generate an output optical beam. The light source includesa plurality of semiconductor sources configured to generate an inputoptical beam, a multiplexer configured to receive at least a portion ofthe input optical beam and to form an intermediate optical beam, and oneor more fibers configured to receive at least a portion of theintermediate optical beam and to form the output optical beam, whereinat least a portion of the one or more fibers comprises a fused silicafiber, wherein the output optical beam comprises one or more opticalwavelengths, and wherein the light source and output optical beam arepulsed. The system includes a light beam set-up configured to receive atleast a portion of the output optical beam and to form a filteredoptical beam, a measurement apparatus configured to receive a receivedportion of the filtered optical beam and to deliver a delivered portionof the filtered optical beam to a sample, and a receiver configured toreceive at least a portion of a spectroscopy output beam generated fromthe sample by the delivered portion of the filtered optical beam. Thereceiver is further configured to perform time-gated detection, to besynchronized with one or more pulses from the light source, and toprocess the at least a portion of the spectroscopy output beam togenerate an output signal. The output signal is based at least in parton a chemical composition of the sample, wherein the light source andreceiver are remote from the sample.

In one embodiment, a near-infrared or SWIR super-continuum (SC) sourcemay be used as the light source for spectroscopy, active remote sensing,or hyper-spectral imaging. One embodiment of the SWIR light source maybe an all-fiber integrated SWIR SC source, which leverages the maturetechnologies from the telecommunications and fiber optics industry.Exemplary fiber-based super-continuum sources may emit light in thenear-infrared or SWIR between approximately 1.4-1.8 microns, 2-2.5microns, 1.4-2.4 microns, 1-1.8 microns, or any number of other bands.In particular embodiments, the detection system may be a dispersivespectrometer, a Fourier transform infrared spectrometer, or ahyper-spectral imaging detector or camera. In addition, reflection ordiffuse reflection light spectroscopy may be implemented using the SWIRlight source, where the spectral reflectance can be the ratio ofreflected energy to incident energy as a function of wavelength.

In one embodiment, a device includes a light source comprising aplurality of light emitting diodes (LEDs), each of the LEDs configuredto generate an output optical beam having one or more opticalwavelengths, wherein at least a portion of the one or more opticalwavelengths is a near-infrared wavelength between 700 nanometers and2500 nanometers. The light source is configured to improvesignal-to-noise ratio by increasing light intensity relative to aninitial light intensity from at least one of the plurality of LEDs andby increasing pulse rate relative to an initial pulse rate of at leastone of the plurality of LEDs. A lens is positioned to receive at least aportion of at least one of the output optical beams and to deliver alens output beam to tissue. A reflective surface is positioned toreceive and redirect at least a portion of light reflected from thetissue. A detection system is located to receive at least a portion ofthe lens output beam reflected from the tissue and configured togenerate an output signal in response, wherein the detection system isfurther configured to be synchronized to the light source. The detectionsystem is located at a distance from a first one of the plurality ofLEDs and at a different distance from a second one of the plurality ofLEDs such that the detection system generates a first signal from thefirst one of the plurality of LEDs and a second signal from the secondone of the plurality of LEDs, and wherein the output signal is generatedin part by comparing the first and second signals.

In another embodiment, a wearable device for measuring one or morephysiological parameters includes a light source comprising a pluralityof semiconductor sources that are light emitting diodes (LEDs), each ofthe LEDs configured to generate an output optical beam having one ormore optical wavelengths, wherein at least a portion of the one or moreoptical wavelengths is a near-infrared wavelength between 700 nanometersand 2500 nanometers. The light source is configured to increasesignal-to-noise ratio by increasing light intensity from an initiallight intensity for at least one of the plurality of semiconductorsources and by increasing a pulse rate from an initial pulse rate of atleast one of the plurality of semiconductor sources. A lens isconfigured to receive a portion of at least one of the output opticalbeams and to deliver a lens output beam to tissue. A detection systemconfigured to receive at least a portion of the lens output beamreflected from the tissue and to generate an output signal, wherein thedetection system is configured to be synchronized to the light source.The detection system is located at a distance from a first one of theplurality of LEDs and at a different distance from a second one of theplurality of LEDs such that the detection system receives a first signalfrom the first LED and a second signal from the second LED.

In one embodiment, a device includes a light source comprising aplurality of semiconductor sources that are light emitting diodes(LEDs), each of the LEDs configured to generate an output optical beamhaving one or more optical wavelengths, wherein at least a portion ofthe one or more optical wavelengths is a near-infrared wavelengthbetween 700 nanometers and 2500 nanometers. The light source isconfigured to improve a signal-to-noise ratio by increasing lightintensity from at least one of the LEDs relative to an initial lightintensity and by increasing a pulse rate of at least one of the LEDsrelative to an initial pulse rate. A lens is configured to receive aportion of at least one of the output optical beams and to deliver alens output beam to tissue. A reflective surface is configured toreceive and redirect at least a portion of light reflected from thetissue. A detection system is configured to receive at least a portionof the lens output beam reflected from the tissue, wherein the detectionsystem is configured to be synchronized to the light source. Thedetection system is further configured to: capture light while the LEDsare off and convert the captured light into a first signal, capturelight while at least one of the LEDs is on and convert the capturedlight into a second signal, further improve the signal-to-noise ratio ofthe portion of the lens output beam reflected from the tissue bydifferencing the first signal and the second signal, and generate anoutput signal.

In one embodiment, a measurement system includes a light sourceconfigured to generate an output optical beam comprising one or moresemiconductor sources configured to generate an input beam, one or moreoptical amplifiers configured to receive at least a portion of the inputbeam and to deliver an intermediate beam to an output end of the one ormore optical amplifiers, and one or more optical fibers configured toreceive at least a portion of the intermediate beam and to deliver atleast the portion of the intermediate beam to a distal end of the one ormore optical fibers to form a first optical beam. A nonlinear element isconfigured to receive at least a portion of the first optical beam andto broaden a spectrum associated with the at least a portion of thefirst optical beam to at least 10 nm through a nonlinear effect in thenonlinear element to form the output optical beam with an output beambroadened spectrum, wherein at least a portion of the output beambroadened spectrum comprises a short-wave infrared wavelength betweenapproximately 1400 nanometers and approximately 2500 nanometers, andwherein at least a portion of the one or more fibers is a fused silicafiber with a core diameter less than approximately 400 microns. Ameasurement apparatus is configured to receive a received portion of theoutput optical beam and to deliver a delivered portion of the outputoptical beam to a sample for a non-destructive and non-contactmeasurement, wherein the delivered portion of the output optical beam isconfigured to generate a spectroscopy output beam from the sample. Areceiver is configured to receive at least a portion of the spectroscopyoutput beam having a bandwidth of at least 10 nanometers and to processthe portion of the spectroscopy output beam to generate an outputsignal, and wherein at least a part of the delivered portion of theoutput optical beam is at least partially transmitting through apackaging material covering at least a part of the sample, and whereinthe output signal is based on a chemical composition of the sample.

In another embodiment, a measurement system includes a light sourceconfigured to generate an output optical beam comprising a plurality ofsemiconductor sources configured to generate an input optical beam, amultiplexer configured to receive at least a portion of the inputoptical beam and to form an intermediate optical beam, and one or morefibers configured to receive at least a portion of the intermediateoptical beam and to form the output optical beam, wherein the outputoptical beam comprises one or more optical wavelengths. A measurementapparatus is configured to receive a received portion of the outputoptical beam and to deliver a delivered portion of the output opticalbeam to a sample, wherein the delivered portion of the output opticalbeam is configured to generate a spectroscopy output beam from thesample. A receiver is configured to receive at least a portion of thespectroscopy output beam and to process the portion of the spectroscopyoutput beam to generate an output signal, wherein the receiver comprisesa Fourier transform infrared (FTIR) spectrometer or a dispersivespectrometer, and wherein at least a part of the delivered portion ofthe output optical beam is at least partially transmitting through apackaging material covering at least a part of the sample.

In yet another embodiment, a method of measuring includes generating anoutput optical beam comprising generating an input optical beam from aplurality of semiconductor sources, multiplexing at least a portion ofthe input optical beam and forming an intermediate optical beam, andguiding at least a portion of the intermediate optical beam and formingthe output optical beam, wherein the output optical beam comprises oneor more optical wavelengths. The method may also include receiving areceived portion of the output optical beam and delivering a deliveredportion of the output optical beam to a sample, wherein the samplecomprises an organic compound with an overtone or combinationalabsorption band in the wavelength range between approximately 1 micronand approximately 2.5 microns. The method may further include generatinga spectroscopy output beam having a bandwidth of at least 10 nanometersfrom the sample using a Fourier transform infrared (FTIR) spectrometeror a dispersive spectrometer, receiving at least a portion of thespectroscopy output beam, and processing the portion of the spectroscopyoutput beam and generating an output signal.

With the growing obesity epidemic, the number of individuals withdiabetes is increasing dramatically. For example, there are over 200million people who have diabetes. Diabetes control requires monitoringof the glucose level, and most glucose measuring systems availablecommercially require drawing of blood. Depending on the severity of thediabetes, a patient may have to draw blood and measure glucose four tosix times a day. This may be extremely painful and inconvenient for manypeople. In addition, for some groups, such as soldiers in thebattlefield, it may be dangerous to have to measure periodically theirglucose level with finger pricks.

Thus, there is an unmet need for non-invasive glucose monitoring (e.g.,monitoring glucose without drawing blood). The challenge has been that anon-invasive system requires adequate sensitivity and selectivity, alongwith repeatability of the results. Yet, this is a very large market,with an estimated annual market of over $10 B in 2011 forself-monitoring of glucose levels.

One approach to non-invasive monitoring of blood constituents or bloodanalytes is to use near-infrared spectroscopy, such as absorptionspectroscopy or near-infrared diffuse reflection or transmissionspectroscopy. Some attempts have been made to use broadband lightsources, such as tungsten lamps, to perform the spectroscopy. However,several challenges have arisen in these efforts. First, many otherconstituents in the blood also have signatures in the near-infrared, sospectroscopy and pattern matching, often called spectral fingerprinting,is required to distinguish the glucose with sufficient confidence.Second, the non-invasive procedures have often transmitted or reflectedlight through the skin, but skin has many spectral artifacts in thenear-infrared that may mask the glucose signatures. Moreover, the skinmay have significant water and blood content. These difficulties becomeparticularly complicated when a weak light source is used, such as alamp. More light intensity can help to increase the signal levels, and,hence, the signal-to-noise ratio.

As described in this disclosure, by using brighter light sources, suchas fiber-based supercontinuum lasers, super-luminescent laser diodes,light-emitting diodes or a number of laser diodes, the near-infraredsignal level from blood constituents may be increased. By shining lightthrough the teeth, which have fewer spectral artifacts than skin in thenear-infrared, the blood constituents may be measured with lessinterfering artifacts. Also, by using pattern matching in spectralfingerprinting and various software techniques, the signatures fromdifferent constituents in the blood may be identified. Moreover,value-add services may be provided by wirelessly communicating themonitored data to a handheld device such as a smart phone, and thenwirelessly communicating the processed data to the cloud for storing,processing, and transmitting to several locations.

In various embodiments, a measurement system includes a light sourceconfigured to generate an output optical beam that includes one or moresemiconductor sources configured to generate an input beam, one or moreoptical amplifiers configured to receive at least a portion of the inputbeam and to output an intermediate beam from at least one of the one ormore optical amplifiers; and one or more optical fibers configured toreceive at least a portion of the intermediate beam and to communicateat least part of the portion of the intermediate beam to a distal end ofthe one or more optical fibers to form a first optical beam. The lightsource may also include a nonlinear element configured to receive atleast a portion of the first optical beam and to broaden a spectrumassociated with the at least a portion of the first optical beam to atleast 10 nm through a nonlinear effect in the nonlinear element to formthe output optical beam with an output beam broadened spectrum. The atleast a portion of the output beam broadened spectrum comprises anear-infrared wavelength between approximately 700 nm and approximately2500 nm, and at least a portion of the one or more fibers is a fusedsilica fiber with a core diameter less than approximately 400 microns.The system may also include a measurement apparatus configured toreceive a received portion of the output optical beam and to deliver toa sample an analysis output beam, which is a delivered portion of theoutput optical beam and wherein the delivered portion of the outputoptical beam is a spatially coherent beam, and a receiver configured toreceive and process at least a portion of the analysis output beamreflected or transmitted from the sample having a bandwidth of at least10 nanometers and to generate an output signal. In addition, a personaldevice comprising a wireless receiver, a wireless transmitter, adisplay, a microphone, a speaker, one or more buttons or knobs, amicroprocessor and a touch screen may be configured to receive andprocess at least a portion of the output signal, wherein the personaldevice is configured to store and display the processed output signal,wherein at least a portion of the processed output signal is configuredto be transmitted over a wireless transmission link.

In another embodiment, a measurement system includes a light sourcecomprising a plurality of semiconductor sources configured to generatean output optical beam with one or more optical wavelengths, wherein atleast a portion of the one or more optical wavelengths is anear-infrared wavelength between 700 nanometers and 2500 nanometers. Ameasurement apparatus is configured to receive a received portion of theoutput optical beam and to deliver to a sample an analysis output beam,which is a delivered portion of the output optical beam; and a receiveris configured to receive and process at least a portion of the analysisoutput beam reflected or transmitted from the sample and to generate anoutput signal. The system includes a personal device comprising awireless receiver, a wireless transmitter, a display, a microphone, aspeaker, one or more buttons or knobs, a microprocessor and a touchscreen, the personal device configured to receive and process at least aportion of the output signal, wherein the personal device is configuredto store and display the processed output signal, and wherein at least aportion of the processed output signal is configured to be transmittedover a wireless transmission link, and a remote device configured toreceive over the wireless transmission link a received output statuscomprising the at least a portion of the processed output signal, tobuffer the received output status, to process the received output statusto generate processed data and to store the processed data.

Other embodiments may include a measurement system comprising a wearablemeasurement device for measuring one or more physiological parameters,including a light source comprising a plurality of semiconductor sourcesconfigured to generate an output optical beam with one or more opticalwavelengths, wherein at least a portion of the one or more opticalwavelengths is a near-infrared wavelength between 700 nanometers and2500 nanometers. The wearable measurement device is configured toreceive a received portion of the output optical beam and to deliver toa sample an analysis output beam, which is a delivered portion of theoutput optical beam. The wearable measurement device further comprises areceiver configured to receive and process at least a portion of theanalysis output beam reflected or transmitted from the sample and togenerate an output signal. The system also includes a personal devicecomprising a wireless receiver, a wireless transmitter, a display, amicrophone, a speaker, one or more buttons or knobs, a microprocessorand a touch screen, the personal device configured to receive andprocess at least a portion of the output signal, wherein the personaldevice is configured to store and display the processed output signal,and wherein at least a portion of the processed output signal isconfigured to be transmitted over a wireless transmission link and aremote device configured to receive over the wireless transmission linka received output status comprising the at least a portion of theprocessed output signal, to buffer the received output status, toprocess the received output status to generate processed data and tostore the processed data, and wherein the remote device is capable ofstoring a history of at least a portion of the received output statusover a specified period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the present disclosure, and forfurther features and advantages thereof, reference is now made to thefollowing description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 shows the absorbance for two common plastics, polyethylene andpolystyrene.

FIG. 2 illustrates one example of the difference in near-infraredspectrum between an authentic tablet and a counterfeit tablet.

FIG. 3 shows the second derivative of the spectral comparison of Prozacand a similarly formulated generic.

FIG. 4 illustrates an example of the near infrared spectra for differentpure components of a studied drug.

FIG. 5 shows the mid-wave infrared and long-wave infrared absorptionspectra for various illicit drugs.

FIG. 6 shows the absorbance versus wavelength in the near-infraredregion for four classes of illegal drugs.

FIG. 7 illustrates the diffuse reflectance near-infrared spectrum ofheroin samples.

FIG. 8 illustrates the diffuse reflectance near-infrared spectra ofdifferent seized illicit drugs containing heroin of differentconcentrations, along with the spectrum for pure heroin.

FIGS. 9A and 9B list possible band assignments for the various spectralfeatures in pure heroin.

FIG. 10 shows the diffuse reflectance near-infrared spectra of differentcompounds that may be frequently employed as cutting agents.

FIG. 11 provides one example of a flow-chart in the process analyticaltechnology for the pharmaceutical industry.

FIG. 12 illustrates the typical near-infrared spectra of a variety ofexcipients.

FIG. 13 exemplifies the absorbance from the blending process of apharmaceutical compound.

FIG. 14 shows what might be an eventual flow-chart of a smartmanufacturing process.

FIG. 15A illustrates the near-infrared reflectance spectrum of wheatflour.

FIG. 15B shows the near-infrared absorbance spectra obtained indiffusion reflectance mode for a series of whole ‘Hass’ avocado fruit.

FIG. 16A is a schematic diagram of the basic elements of an imagingspectrometer.

FIG. 16B illustrates one example of a typical imaging spectrometer usedin hyper-spectral imaging systems.

FIG. 17 shows one example of the Fourier transform infraredspectrometer.

FIG. 18A shows one example of a dual-beam experimental set-up that maybe used to subtract out (or at least minimize the adverse effects of)light source fluctuations.

FIG. 18B shows the dorsal of the hand, where a differential measurementmay be made to at least partially compensate for or subtract out theskin interference.

FIG. 18C shows the dorsal of the foot, where a differential measurementmay be made to at least partially compensate for or subtract out theskin interference.

FIG. 19 illustrates a block diagram or building blocks for constructinghigh power laser diode assemblies.

FIG. 20 shows a platform architecture for different wavelength rangesfor an all-fiber-integrated, high powered, super-continuum light source.

FIG. 21 illustrates one embodiment for a short-wave infraredsuper-continuum light source.

FIG. 22 shows the output spectrum from the SWIR SC laser of FIG. 21 whenabout a 10 m length of fiber for SC generation is used. This fiber is asingle-mode, non-dispersion shifted fiber that is optimized foroperation near 1550 nm.

FIG. 23A illustrates a high power SWIR-SC laser that may generate lightbetween approximately 1.4-1.8 microns.

FIG. 23B illustrates a high power SWIR-SC laser that may generate lightbetween approximately 2-2.5 microns.

FIG. 23C shows a reflection-spectroscopy based stand-off detectionsystem having an SC laser source.

FIG. 24 schematically shows a medical measurement device as part of apersonal or body area network that communicates with another device(e.g., smart phone or tablet) that communicates with the cloud. Thecloud may in turn communicate information with the user, healthcareproviders, or other designated recipients.

DETAILED DESCRIPTION

As required, detailed embodiments of the present disclosure aredescribed herein; however, it is to be understood that the disclosedembodiments are merely exemplary of the disclosure that may be embodiedin various and alternative forms. The figures are not necessarily toscale; some features may be exaggerated or minimized to show details ofparticular components. Therefore, specific structural and functionaldetails disclosed herein are not to be interpreted as limiting, butmerely as a representative basis for teaching one skilled in the art tovariously employ the present disclosure.

One advantage of optical systems is that they can perform non-contact,stand-off or remote sensing distance spectroscopy of various materials.As an example, optical systems can be used for identification ofcounterfeit drugs, detection of illicit drugs, or process control in thepharmaceutical industry, especially when the sensing is to be done atremote or stand-off distances in a non-contact, rapid manner. Ingeneral, the near-infrared region of the electromagnetic spectrum coversbetween approximately 0.7 microns (700 nm) to about 2.5 microns (2500nm). However, it may also be advantageous to use just the short-waveinfrared (SWIR) between approximately 1.4 microns (1400 nm) and about2.5 microns (2500 nm). One reason for preferring the SWIR over theentire NIR may be to operate in the so-called “eye safe” window, whichcorresponds to wavelengths longer than about 1400 nm. Therefore, for theremainder of the disclosure the SWIR will be used for illustrativepurposes. However, it should be clear that the discussion that followscould also apply to using the near infrared—NIR—wavelength range, orother wavelength bands.

In particular, wavelengths in the eye safe window may not transmit downto the retina of the eye, and therefore, these wavelengths may be lesslikely to create permanent eye damage from inadvertent exposure. Thenear-infrared wavelengths have the potential to be dangerous, becausethe eye cannot see the wavelengths (as it can in the visible), yet theycan penetrate and cause damage to the eye. Even if a practitioner is notlooking directly at the laser beam, the practitioner's eyes may receivestray light from a reflection or scattering some surface. Hence, it canalways be a good practice to use eye protection when working aroundlasers. Since wavelengths longer than about 1400 nm are substantiallynot transmitted to the retina or substantially absorbed in the retina,this wavelength range is known as the eye safe window. For wavelengthslonger than 1400 nm, in general only the cornea of the eye may receiveor absorb the light radiation.

The SWIR wavelength range may be particularly valuable for identifyingmaterials based on their chemical composition because the wavelengthrange comprises overtones and combination bands for numerous chemicalbonds. For example, in the SWIR numerous hydro-carbon chemical compoundshave overtone and combinational bands, along with oxygen-hydrogen andcarbon-oxygen compounds. Thus, gases, liquids and solids that comprisethese chemical compounds may exhibit spectral features in the SWIRwavelength range. In a particular embodiment, the spectra of organiccompounds may be dominated by the C—H stretch. The C—H stretchfundamental occurs near 3.4 microns, the first overtone is near 1.7microns, and a combination band occurs near 2.3 microns.

One embodiment of remote sensing that is used to identify and classifyvarious materials is so-called “hyper-spectral imaging.” Hyper-spectralsensors may collect information as a set of images, where each imagerepresents a range of wavelengths over a spectral band. Hyper-spectralimaging may deal with imaging narrow spectral bands over anapproximately continuous spectral range. As an example, inhyper-spectral imaging a lamp may be used as the light source. However,the incoherent light from a lamp may spatially diffract rapidly, therebymaking it difficult to perform spectroscopy at stand-off distances orremote distances. Therefore, it would be advantageous to have abroadband light source covering the SWIR that may be used in place of alamp to identify or classify materials in remote sensing or stand-offdetection applications.

As used throughout this document, the term “couple” and or “coupled”refers to any direct or indirect communication between two or moreelements, whether or not those elements are physically connected to oneanother. As used throughout this disclosure, the term “spectroscopy”means that a tissue or sample is inspected by comparing differentfeatures, such as wavelength (or frequency), spatial location,transmission, absorption, reflectivity, scattering, fluorescence,refractive index, or opacity. In one embodiment, “spectroscopy” may meanthat the wavelength of the light source is varied, and the transmission,absorption, fluorescence, or reflectivity of the tissue or sample ismeasured as a function of wavelength. In another embodiment,“spectroscopy” may mean that the wavelength dependence of thetransmission, absorption, fluorescence or reflectivity is comparedbetween different spatial locations on a tissue or sample. As anillustration, the “spectroscopy” may be performed by varying thewavelength of the light source, or by using a broadband light source andanalyzing the signal using a spectrometer, wavemeter, or opticalspectrum analyzer.

As used throughout this document, the term “fiber laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein at least a part of the laser comprises an optical fiber. Forinstance, the fiber in the “fiber laser” may comprise one of or acombination of a single mode fiber, a multi-mode fiber, a mid-infraredfiber, a photonic crystal fiber, a doped fiber, a gain fiber, or, moregenerally, an approximately cylindrically shaped waveguide orlight-pipe. In one embodiment, the gain fiber may be doped with rareearth material, such as ytterbium, erbium, and/or thulium. In anotherembodiment, the mid-infrared fiber may comprise one or a combination offluoride fiber, ZBLAN fiber, chalcogenide fiber, tellurite fiber, orgermanium doped fiber. In yet another embodiment, the single mode fibermay include standard single-mode fiber, dispersion shifted fiber,non-zero dispersion shifted fiber, high-nonlinearity fiber, and smallcore size fibers.

As used throughout this disclosure, the term “pump laser” refers to alaser or oscillator that has as an output light or an optical beam,wherein the output light or optical beam is coupled to a gain medium toexcite the gain medium, which in turn may amplify another input opticalsignal or beam. In one particular example, the gain medium may be adoped fiber, such as a fiber doped with ytterbium, erbium and/orthulium. In one embodiment, the “pump laser” may be a fiber laser, asolid state laser, a laser involving a nonlinear crystal, an opticalparametric oscillator, a semiconductor laser, or a plurality ofsemiconductor lasers that may be multiplexed together. In anotherembodiment, the “pump laser” may be coupled to the gain medium by usinga fiber coupler, a dichroic mirror, a multiplexer, a wavelength divisionmultiplexer, a grating, or a fused fiber coupler.

As used throughout this document, the term “super-continuum” and or“supercontinuum” and or “SC” refers to a broadband light beam or outputthat comprises a plurality of wavelengths. In a particular example, theplurality of wavelengths may be adjacent to one-another, so that thespectrum of the light beam or output appears as a continuous band whenmeasured with a spectrometer. In one embodiment, the broadband lightbeam may have a bandwidth of at least 10 nm. In another embodiment, the“super-continuum” may be generated through nonlinear opticalinteractions in a medium, such as an optical fiber or nonlinear crystal.For example, the “super-continuum” may be generated through one or acombination of nonlinear activities such as four-wave mixing, parametricamplification, the Raman effect, modulational instability, andself-phase modulation.

As used throughout this disclosure, the terms “optical light” and or“optical beam” and or “light beam” refer to photons or light transmittedto a particular location in space. The “optical light” and or “opticalbeam” and or “light beam” may be modulated or unmodulated, which alsomeans that they may or may not contain information. In one embodiment,the “optical light” and or “optical beam” and or “light beam” mayoriginate from a fiber, a fiber laser, a laser, a light emitting diode,a lamp, a pump laser, or a light source.

As used throughout this disclosure, the term “remote sensing” mayinclude the measuring of properties of an object from a distance,without physically sampling the object, for example by detection of theinteractions of the object with an electromagnetic field. In oneembodiment, the electromagnetic field may be in the optical wavelengthrange, including the infrared or SWIR. One particular form of remotesensing may be stand-off detection, which may range exemplary fromnon-contact up to hundreds of meters away.

Identification of Counterfeit Drugs

Pharmaceutical counterfeiting is a growing and significant issue for thehealthcare community as well as the pharmaceutical industry worldwide.As a result of counterfeiting, users may be threatened by substandarddrug quality or harmful ingredients, and legitimate companies may losesignificant revenues. The definition for “counterfeit drug” by the WorldHealth Organization was as follows: “A counterfeit medicine is one whichis deliberately and fraudulently mislabeled with respect to identityand/or source. Counterfeiting can apply to both branded and genericproducts and counterfeit products may include products with the correctingredients or with the wrong ingredients, without active ingredients,with insufficient active ingredient or with fake packaging.” Later thisdefinition was slightly modified, “Counterfeiting in relation tomedicinal products means the deliberate and fraudulent mislabeling withrespect to the identity, composition and/or source of a finishedmedicinal product, or ingredient for the preparation of a medicinalproduct.”

A rapid screening technique such as near-infrared or SWIR spectroscopycould aid in the search for and identification of counterfeit drugs. Inparticular, using a non-lamp based light source could lead tocontact-free control and analysis of drugs. In a particular embodiment,remote sensing, stand-off detection, or hyper-spectral imaging may beused for process control or counterfeit drug identification in a factoryor manufacturing setting, or in a retail, wholesale, or warehousesetting. In one embodiment, the light source for remote sensing maydirect the light beam toward the region of interest (e.g., conveyorbelt, stocking shelves, boxes or cartons, etc), and the diffusereflected light may then be measured using a detection system. Variouskinds of SWIR light sources will be discussed later in this disclosure.The detection system may comprise, in one embodiment, a spectrometerfollowed by one or more detectors. In another embodiment, the detectionsystem may be a dispersive element (examples include prisms, gratings,or other wavelength separators) followed by one or more detectors ordetector arrays. In yet another embodiment, the detection system maycomprise a Fourier transform infrared spectrometer. These are merelyspecific examples of the detection system, but combinations of these orother detection systems may also be used and are contemplated within thescope of this disclosure.

For monitoring drugs, the SWIR light source and the detection systemcould be used in transmission, reflection, fluorescence, or diffusereflection. Also, different system configurations may also be used andare included in the scope of this disclosure. For example, the lightsource and detection system may be placed in a fixed location, and forreflection the light source and detectors may be close to one another,while for transmission the light source and detectors may be atdifferent locations. The region of interest may be surveyed, and thelight beam may also be scanned to cover an area larger than the lightsource beam. In yet another embodiment, the system could be placed on avehicle such as an automobile or a truck, or the light source could beplaced on one vehicle, while the detection system is on another vehicle.If the light source and detection system are compact and lightweight,they might even be carried by a person in the field, either in theirhands or in a backpack.

Another advantage of using the near-infrared or SWIR is that most drugpackaging materials are at least partially transparent in thiswavelength range, so that drug compositions may be detected andidentified through the packaging non-destructively. As an example, SWIRlight could be used to see through plastics, since the signature forplastics can be subtracted off and there are large wavelength windowswhere the plastics are transparent. FIG. 1 illustrates the absorbance100 for two common plastics: polyethylene 101 and polystyrene 102.Because of the hydro-carbon bonds, there are absorption features near1.7 microns and 2.2-2.5 microns. In general, the absorption bands in thenear infrared are due to overtones and combination bands for variousfunctional group vibrations, including signals from C—H, O—H, C═O, N—H,—COOH, and aromatic C—H groups. It may be difficult to assign anabsorption band to a specific functional group due to overlapping ofseveral combinations and overtones. However, with advancements incomputational power and chemometrics or multivariate analysis methods,complex systems may be better analyzed. In one embodiment, usingsoftware analysis tools the absorption spectrum may be converted to itssecond derivative equivalent. The spectral differences may permit afast, accurate, non-destructive and reliable identification ofmaterials. Although particular derivatives are discussed, othermathematical manipulations may be used in the analysis, and these othertechniques are also intended to be covered by this disclosure.

Spectroscopy in the near-infrared or SWIR may be sensitive to both thechemical and physical nature of the sample composition and may beperformed rapidly with minimal sample preparation. For example,near-infrared or SWIR spectroscopy may be used to study the homogeneityof powder samples, particle size determinations, product composition,the determination of the concentrations and distribution of componentsin solid tablets and content uniformity, among other applications. Inyet other embodiments, applications include tablet identification,determination of moisture, residual solvents, active ingredient potency,the study of blending operations, and the detection of capsuletampering.

FIG. 2 illustrates one example of the difference in near-infraredspectrum 200 between an authentic tablet and a counterfeit tablet. Twogrades of film coated tablets comprising drugs were investigated: curve201 is the genuine drug, while 202 is a counterfeit drug. These twogrades of capsules have noticeably different contents, and thedifferences are apparent in the near-infrared or SWIR spectra. In somecases the differences may not be as distinct. For these cases, moresignal processing may be necessary to distinguish between samples.

In another embodiment, it may be advantageous to take a first, second orhigher order derivative to elucidate the difference between real andcounterfeit drugs. For example, FIG. 3 shows the second derivative 300of the spectral comparison of Prozac 301 and a similarly formulatedgeneric 302, which had a fluoxetine hydrochloride (10 mg). Although thereflectance curves from the two samples are close and, therefore,difficult to distinguish, the second derivative of the data helps tobring out the differences more clearly. Although a second derivative isused in this example, any number of signal processing algorithms andmethods may be used, and these are also intended to be covered by thisdisclosure. For example, partial least square algorithms, multivariatedata analysis, principal component analysis, or chemometric software maybe implemented without departing from the scope of this disclosure.

In yet another embodiment, near-infrared or SWIR spectroscopy may beused to measure and calibrate various pharmaceutical formulations basedon the active pharmaceutical ingredients and excipients. An excipientmay be a pharmacologically inactive substance used as a carrier for theactive ingredients of a medication. In some cases, the active substancemay not be easily administered and/or absorbed by the human body; insuch cases the active ingredient may be dissolved into or mixed with anexcipient. Also, excipients are also sometimes used to bulk upformulations that contain very potent active ingredients, to allow forconvenient and accurate dosage. In addition to their use in thesingle-dosage quantity, excipients can be used in the manufacturingprocess to aid in the handling of the active substance concerned.

FIG. 4 shows an example of the near-infrared spectra 400 for differentpure components of a studied drug. The spectrum for the activepharmaceutical ingredient (API) 401 is plotted, along with the spectrafor five different excipients 402, 403, 404, 405 and 406. Each spectrumhas been baseline shifted to avoid overlapping. The near-infraredspectra have been obtained by averaging the spectra of each pixel of anarea of a hyper-spectral image. As FIG. 4 shows, each of the chemicalcompositions have a distinct spectrum, and the composition of a drug maybe decomposed into its constitutive ingredients. These are just someexamples of how near-infrared or SWIR spectroscopy may be applied tocounterfeit drug detection, but other methods and analysis techniquesmay also be used without departing from the scope of this disclosure. Asone other example, once the active pharmaceutical ingredient and theexcipients spectral distribution of a drug formulation are understood,feedback may be provided of this information to the drug developmentstages.

Rapid Screening for Illicit Drugs

Thus, FIGS. 2-4 show that near-infrared or SWIR spectroscopy may be usedto identify counterfeit drugs. More generally, various materialsincluding illicit drugs, explosives, fertilizers, vegetation, and paintshave features in the near-infrared and SWIR that can be used to identifythe various samples, and these applications are also intended to bewithin the scope of this disclosure. Although stronger features may befound in the mid-infrared, the near-infrared may be easier to measuredue to higher quality detection systems, more mature fiber optics andlight sources, and transmission through atmospheric transmissionwindows. Because of these distinct spectral signatures, these materialscould also be detected using active remote sensing, hyper-spectralimaging, or near-infrared or SWIR spectroscopy. As just another example,illicit drugs may be detectable using remote sensing, hyper-spectralimaging, or near-infrared spectroscopy. FIG. 5 shows the mid-waveinfrared and long-wave infrared absorption spectra 500 for variousillicit drugs. The absorbance for cocaine 501, methamphetamine 502, MDMA(ecstasy) 503, and heroin 504 are plotted versus wavelength fromapproximately 2.5-20 microns. Although the fundamental resonances forthese drugs may lie in the longer wavelength regions, there arecorresponding overtones and combination bands in the SWIR andnear-infrared wavelength range. Therefore, the active remote sensing,hyper-spectral imaging, or near-infrared or SWIR spectroscopy techniquesdescribed herein may also be applicable to detecting illicit drugs fromaircraft, vehicles, or hand held devices.

The diffuse reflectance technique may be useful with near-infrared orSWIR spectroscopy for rapid identification of illegal drugs due tosimple handling and simple use of a search data library created usingnear-infrared diffuse reflectance. For instance, FIG. 6 illustrates theabsorbance 600 versus wavelength in the near-infrared region for fourclasses of illegal drugs. In particular, the spectra are shown formethamphetamine (MA) 601, amphetamine (AP) 602, MDMA (street name:ecstasy) 603, and MDA (street name: the love drug) 604. Each of theillegal drugs have unique spectral features in the near-infrared andSWIR. Also, comparing the mid-infrared spectrum for MDMA (503 in FIG. 5)with the near-infrared spectrum for MDMA (603 in FIG. 6), it seems clearthat the near-infrared region shows overtones and combination bands thatshould be discernible. Referring to FIG. 6, sample identification may beaccomplished by using the region (indicated by the arrows) where thespectral absorptions may provide specific peaks depending on the drugcomponent.

In another embodiment, FIG. 7 shows the diffuse reflectancenear-infrared spectrum 700 of heroin samples. Heroin, the 3,6-diacetylderivative of morphine (hence diacetyl-morphine) is an opiate drugsynthesized from morphine, which is usually a naturally occurringsubstance extracted from the seedpod of certain varieties of poppyplants. In particular, 701 is the near-infrared spectrum for an illicitstreet drug sample, while 702 is the spectra for a pure heroin standard.The difference between the spectra may arise at least in part fromcutting agents. The inset 703 shows the molecular structure for heroin.As in the other examples, the absorption in the near-infrared range iscaused by overtone and combination vibrations of O—H, C—H, N—H and C═Ogroups, which exhibit their fundamental molecular stretching and bendingabsorption in the mid-infrared range (c.f., the mid-infrared spectrumfor heroin is shown 504 in FIG. 5). These overtone and combination bandsdo not behave in a simple way, making the near-infrared spectra complexand harder to directly interpret. Also, although the near-infraredsignatures may be weaker in magnitude, they are probably easier todetect in the near-infrared, and the sample preparation may also be muchsimpler in the near-infrared. Moreover, for remote sensing, thenear-infrared may be preferable because of atmospheric transmissionwindows between approximately 1.4-1.8 microns and 2-2.5 microns.

Pure heroin may be a white powder with a bitter taste that is rarelysold on the streets, while illicit heroin may be a powder varying incolor from white to dark brown due to impurities left from themanufacturing process or the presence of additives. The purity of streetheroin may also vary widely, as the drug can be mixed with other whitepowders. The impurity of the drug may often make it difficult to gaugethe strength of the dosage, which runs the risk of overdose. One nicefeature of near-infrared or SWIR spectroscopy is that the technique maybe used in a non-destructive, non-contact manner to determine rapidlythe concentration of compounds present in complex samples at percentagelevels with very little sample preparation. In a particular embodiment,FIG. 8 illustrates the diffuse reflectance near-infrared spectra 800 ofdifferent seized illicit drugs containing heroin (between 10.7 and21.8%) compared with the spectrum of pure heroin 801. Curve 802 is for21.8% by weight, curve 803 is 13.2% by weight, curve 804 is 17% byweight, and curve 805 is 10.7% by weight of heroin. The spectra havebeen shifted along the vertical axis to better illustrate thedifferences.

Although quite complex in the near-infrared, it may be possible toidentify from the pure heroin near-infrared spectrum (801 in FIG. 8 or702 in FIG. 7) the main wavelengths related to the most commonfunctional groups in heroin. For example, FIG. 9 lists possible bandassignments 900 for the various spectral features in pure heroin. As canbe seen from FIG. 9, the absorption in the near-infrared may be mainlydue to overtone and combination bands associated with O—H, C—H, N—H andC=0 groups.

As can be appreciated from FIG. 8, there may be significant differencesbetween the spectrum of pure heroin and sample spectra. Thesedifferences may be due to the presence of different compounds used ascutting agents, which can affect the shape and intensity of thenear-infrared signals. FIG. 10 illustrates the diffuse reflectancenear-infrared spectra 1000 of different compounds that may be frequentlyemployed as cutting agents. In the bottom of FIG. 10 are shown thespectra 1008 for pure heroin and the spectra 1007 for a seized illicitstreet drug sample comprising 21.8% of heroin. The spectra for variouscutting agents include: 1001 for flour, 1002 for talcum powder, 1003 forchalk, 1004 for acetylsalicylic acid, 1005 for caffeine, and 1006 forparacetamol. Thus, near-infrared or SWIR spectroscopy may be used towork back to the composition of an unknown drug. Although particularexamples of counterfeit and illicit drugs have been described, thenear-infrared or SWIR spectroscopy (including diffuse reflectance,reflectance, fluorescence or transmission) may also be applied to theidentification of other drugs and substances without departing from thescope of this disclosure. This spectroscopy may be usednon-destructively and non-contact over stand-off distances or in remotesensing distances, whether from an airborne, vehicle, hand-held, orstationary platform.

Process Analytical Technology (PAT)

One definition of process analytical technology, PAT, is “a system fordesigning, analyzing and controlling manufacturing through timelyevaluations (i.e., during processing) of significant quality andperformance attributes of raw and in-process materials and processes,with the goal of ensuring final product quality.” Near-infrared or SWIRspectroscopy may have applications in the PAT of the pharmaceuticalindustry by providing, for example, quantitative analysis of multiplecomponents in a sample and in pack quantification of drugs informulation, as well as quality of a drug and quality control of complexexcipients used in formulation. The PAT process may benefit fromnear-infrared or SWIR spectroscopy for some steps, such as: raw materialidentification, active pharmaceutical ingredient applications, drying,granulation, blend uniformity and content uniformity. Some of thestrengths of near-infrared or SWIR spectroscopy include: radiation hasgood penetration properties, and, thus, minimal sample preparation maybe required; measurement results may be obtained rapidly, andsimultaneous measurements may be obtained for several parameters;non-destructive methods with little or no chemical waste; and organicchemicals that comprise most pharmaceutical products have unique spectrain the near-infrared and SWIR ranges, for example.

FIG. 11 shows one example of a flow-chart 1100 in the PAT for thepharmaceutical industry. While the center shows the steps of themanufacturing process 1101, the top and bottom sides show wherenear-infrared spectroscopy could be applicable for lab use 1102 (top) orin process monitoring control 1103 (bottom). Indeed, near-infrared orSWIR spectroscopy has the potential to benefit almost every step in themanufacturing process. Just to provide a few examples of usingnear-infrared or SWIR spectroscopy in the PAT process, the raw materialtesting and blending process will be examined briefly.

At the commencement of manufacture of a drug product, it may be requiredto identify the correct material and grade of the pharmaceuticalexcipients to be used in the formulation. FIG. 12 illustrates thetypical near-infrared spectra 1200 for a variety of excipients. Includedin the graph 1200 are spectra for: magnesium stearate 1201, sorbitol1202, mannitol 1203, talc 1204, lactose 1205, starch 1206, maltodextrin1207, and microcrystalline cellulose 1208. A suitable spectral databasemay be used to rapidly identify and qualify excipients. One nice aspectof the spectroscopy is that the near-infrared and SWIR are sensitive toboth the physical and chemical characteristics of the samples.

One of the next steps in the manufacture of a dosage form is theblending together of the active component with the excipients to producea homogeneous blend. In one embodiment, the near-infrared or SWIRspectroscopy apparatus may comprise a fiber-optic probe, which may, forexample, interface with the blending vessel. For such a fiber-opticprobe, near infrared or SWIR spectra may be collected in real-time froma blending process. FIG. 13 exemplifies the absorbance 1300 from theblending process. Although the initial spectra 1301 shows differencesfrom the eventual spectra, as the process continues the blend convergesto the final spectra 1302 and continues to overlap that spectra. Similarconverging or overlapping spectra may also be used to check the productuniformity at the end of the process. The near-infrared spectra may beacquired in real-time; and, using appropriate data pre-processing andchemometric analysis, blend homogeneity plots may be derived, such as1300.

One goal of the manufacturing process and PAT may be the concept of a“smart” manufacturing process, which may be a system or manufacturingoperation responding to analytical data generated in real-time. Such asystem may also have an in-built “artificial intelligence” as decisionsmay be made whether to continue a manufacturing operation. For example,with respect to the raw materials, integration of the qualitymeasurement into smart manufacturing processes could be used to improvemanufacturing operations by ensuring that the correct materials of theappropriate quality are used in the manufacture. Similarly, a smartblender would be under software control and would respond to thereal-time spectral data collected.

FIG. 14 illustrates what might be an eventual flow-chart 1400 of a smartmanufacturing process. The manufacturing process 1401 may have as inputthe process feed 1402 and result in a process output 1403. A processcontroller 1404 may at least partially control the manufacturing process1401, and the controller 1404 may receive inputs from the closed loopcontrol (process parameters) 1405 as well as the on-line monitoring ofprocess parameters 1406. The feedback loops in the process could refinethe manufacturing process 1401 and improve the quality of the processoutput 1403. These are particular embodiments of the use ofnear-infrared or SWIR spectroscopy in the PAT of the pharmaceuticalindustry, but other variations, combinations, and methods may also beused and are intended to be covered by this disclosure, such as use inmanufacture of plastics or food industry goods.

The discussion thus far has centered on use of near-infrared or SWIRspectroscopy in applications such as identification of counterfeitdrugs, detection of illicit drugs, and pharmaceutical process control.Although drugs and pharmaceuticals are one example, many other fieldsand applications may also benefit from the use of near infrared or SWIRspectroscopy, and these may also be implemented without departing fromthe scope of this disclosure. As just another example, near-infrared orSWIR spectroscopy may also be used as an analytic tool for food qualityand safety control. Applications in food safety and quality assessmentinclude contaminant detection, defect identification, constituentanalysis, and quality evaluation. The techniques described in thisdisclosure are particularly valuable when non-destructive testing isdesired at stand-off or remote distances.

In one example, near-infrared or SWIR spectroscopy may be used in cerealbreeding. The breeding purposes may require knowledge on bothcomposition and functional properties of grain, while the functionalityof wheat grain is an issue for wheat breeders. Most of the wheatfunctionality parameters depend on the protein-proteinase complex ofwheat grain, as well as the condition of the carbohydrate complex. FIG.15A illustrates the near-infrared reflectance spectrum 1500 of wheatflour. Since these samples are complex in composition, several organicbonds involving hydrogen vibrate to produce overlapped spectral bands.Thus, the resulting spectrum 1500 appears like a wavy line withoutclearly defined features. Analytical methods based on this type ofspectroscopy may have the potential to improve the quality of finalcereal products by testing the products through the entire productionprocess in the processing industry.

In yet another embodiment, near-infrared or SWIR spectroscopy may beused for the assessment of fruit and vegetable quality. Most commercialquality classification systems for fruit and vegetables are based onexternal features of the product, such as shape, color, size, weight andblemishes. However, the external appearance of most fruit is generallynot an accurate guide to the internal eating quality of the fruit. As anexample, for avocado fruit the external color is not a maturitycharacteristic, and its smell is too weak and appears later in itsmaturity stage. Analysis of the near-infrared or SWIR absorption spectramay provide qualitative and quantitative determination of manyconstituents and properties of horticulture produce, including oil,water, protein, pH, acidity, firmness, and soluble solids content ortotal soluble solids of fresh fruits. FIG. 15B shows the near-infraredabsorbance spectra 1550 obtained in diffusion reflectance mode for aseries of whole ‘Hass’ avocado fruit. Four oil absorption bands are near2200-2400 nm (CH₂ stretch bend and combinations), with weaker absorptionaround 750 nm, 1200 nm, and 900-930 nm ranges. On the other hand, near1300-1750 nm range may be useful for determining the protein and oilcontent. The 900-920 nm absorbance band may be useful for sugardetermination. Although described in the context of grains, fruits, andvegetables, the near-infrared or SWIR spectroscopy may also be valuablefor other food quality control and assessment, such as measuring theproperties of meats. These and other applications also fall within thescope of this disclosure.

Natural gas may be a hydro-carbon gas mixture comprising primarilymethane, with other hydro-carbons, carbon dioxide, nitrogen and hydrogensulfide. Natural gas is important because it is an important energysource to provide heating and electricity. Moreover, it may also be usedas fuel for vehicles and as a chemical feedstock in the manufacture ofplastics and other commercially important organic chemicals. Althoughmethane is the primary component of natural gas, to uniquely identifynatural gas through spectroscopy requires monitoring of both methane andethane. If only methane is used, then areas like cow pastures could bemistaken for natural gas fields or leaks. More specifically, the typicalcomposition of natural gas is as follows:

Component Range(mole %) Methane 87.0-96.0 Ethane 1.5-5.1 Propane 0.1-1.5Iso-butane 0.01-0.3  Normal-butane 0.01-0.3  Iso-pentane Trace-0.14Normal-pentane Trace-0.04 Hexanes plus Trace-0.06 Nitrogen 0.7-5.6Carbon dioxide 0.1-1.0 Oxygen 0.01-0.1  Hydrogen Trace-0.02

Detection Systems

The near-infrared or SWIR spectroscopy system, remote sensing system orhyper-spectral imaging system may be on an airborne platform, mounted ona vehicle, a stationary transmission or reflection set-up, or even heldby a human for a compact system. For such a system, there arefundamentally two hardware parts: the transmitter or light source andthe detection system. Between the two, perhaps in a transmission orreflection setting, may be the sample being tested or measured.Moreover, the output from the detection system may go to a computationalsystem, comprising computers or other processing equipment. The outputfrom the computational system may be displayed graphically as well aswith numerical tables and perhaps an identification of the materialcomposition. These are just some of the parts of the systems, but otherelements may be added or be eliminated, and these modifiedconfigurations are also intended to be covered by this disclosure.

By use of an active illuminator, a number of advantages may be achieved.First, stand-off or remote distances may be achieved if a non-lampsystem is used—i.e., if the beam does not rapidly diffract. Also, highersignal-to-noise ratios may be achieved. For example, one way to improvethe signal-to-noise ratio would be to use modulation and lock-intechniques. In one embodiment, the light source may be modulated, andthen the detection system would be synchronized with the light source.In a particular embodiment, the techniques from lock-in detection may beused, where narrow band filtering around the modulation frequency may beused to reject noise outside the modulation frequency. In anotherembodiment, change detection schemes may be used, where the detectionsystem captures the signal with the light source on and with the lightsource off. Again, for this system the light source may be modulated.Then, the signal with and without the light source is differenced.Change detection may help to identify objects that change in the fieldof view. In the following some exemplary detection systems aredescribed.

In one embodiment, a SWIR camera or infrared camera system may be usedto capture the images. The camera may include one or more lenses on theinput, which may be adjustable. The focal plane assemblies may be madefrom mercury cadmium telluride material (HgCdTe), and the detectors mayalso include thermo-electric coolers. Alternately, the image sensors maybe made from indium gallium arsenide (InGaAs), and CMOS transistors maybe connected to each pixel of the InGaAs photodiode array. The cameramay interface wirelessly or with a cable (e.g., USB, Ethernet cable, orfiber optics cable) to a computer or tablet or smart phone, where theimages may be captured and processed. These are a few examples ofinfrared cameras, but other SWIR or infrared cameras may be used and areintended to be covered by this disclosure.

In another embodiment, an imaging spectrometer may be used to detect thelight received from the sample. For example, FIG. 16A shows a schematicdiagram 1600 of the basic elements of an imaging spectrometer. The inputlight 1601 from the sample may first be directed by a scanning mirrorand/or other optics 1602. An optical dispersing element 1603, such as agrating or prism, in the spectrometer may split the light into manynarrow, adjacent wavelength bands, which may then be passed throughimaging optics 1604 onto one or more detectors or detector arrays 1605.Some sensors may use multiple detector arrays to measure hundreds ofnarrow wavelength bands.

An example of a typical imaging spectrometer 1650 used in hyper-spectralimaging systems is illustrated in FIG. 16B. In this particularembodiment, the input light may be directed first by a tunable mirror1651. A front lens 1652 may be placed before the entrance slit 1653 andthe collector lens 1654. In this embodiment, the dispersing element is aholographic grating with a prism 1655, which separates the differentwavelength bands. Then, a camera lens 1656 may be used to image thewavelengths onto a detector or camera 1657.

FIGS. 16 provide particular examples, but some of the elements may notbe used, or other elements may be added, and these are also intended tobe covered by this disclosure. For instance, a scanning spectrometer maybe used before the detector, where a grating or dispersive element isscanned to vary the wavelength being measured by the detector. In yetanother embodiment, filters may be used before one or more detectors toselect the wavelengths or wavelength bands to be measured. This may beparticularly useful if only a few bands or wavelengths are to bemeasured. The filters may be dielectric filters, Fabry-Perot filters,absorption or reflection filters, fiber gratings, or any otherwavelength selective filter. In one embodiment, a wavelength divisionmultiplexer, WDM, may be used followed by one or more detectors ordetector arrays. One example of a planar wavelength division multiplexermay be a waveguide grating router or an arrayed waveguide grating. TheWDM may be fiber coupled, and detectors may be placed directly at theoutput or the detectors may be coupled through fibers to the WDM. Someof these components may also be combined with the configurations in FIG.16.

While the above detection systems could be categorized as single pathdetection systems, it may be advantageous in some cases to usemulti-path detection systems. In one embodiment, a detection system froma Fourier transform infrared spectrometer, FTIR, may be used. Thereceived light may be incident on a particular configuration of mirrors,called a Michelson interferometer, that allows some wavelengths to passthrough but blocks others due to wave interference. The beam may bemodified for each new data point by moving one of the mirrors, whichchanges the set of wavelengths that pass through. This collected data iscalled an interferogram. The interferogram is then processed, typicallyon a computing system, using an algorithm called the Fourier transform.One advantageous feature of FTIR is that it may simultaneously collectspectral data in a wide spectral range.

FIG. 17 illustrates one example of the FTIR spectrometer 1700. Lightfrom the near-infrared or SWIR light source 1701 may be collimated anddirected to a beam splitter 1702. In one embodiment, the beam splitter1702 may be a 50:50 beam splitter. One portion of the beam 1703 may bereflected toward a stationary mirror 1704, while the other portion ofthe beam 1705 may be transmitted towards a moving mirror 1706. Light maybe reflected from the two mirrors 1704, 1706 back to the beam splitter1702, and then a portion of the recombined beam 1707 may be directedtoward the sample 1708. The recombined beam 1707 may be focused onto thesample 1708, in one embodiment. On leaving the sample 1708, the lightmay be refocused or at least collected at a detector 1709. A backgroundinterferogram may be obtained by using the set-up 1700 without a samplein the chamber 1708. When a sample is inserted into 1708, the backgroundinterferogram may be modulated by the presence of absorption bands inthe sample. The FTIR spectrometer may have several advantages comparedto a scanning (dispersive) spectrometer. Since all the wavelengths maybe collected simultaneously, the FTIR may result in a highersignal-to-noise ratio for a given scan time or a shorter scan time for agiven resolution. Moreover, unlike a spectrometer where a slit may limitthe amount of the beam detected, the FTIR may accommodate the entirediameter of the beam coming from the light source 1701. Theconfiguration 1700 is one example of an FTIR, but other configurationsmay also be used, and these are also intended to be covered by thisdisclosure.

In yet another example of multi-beam detection systems, a dual-beamset-up 1800 such as in FIG. 18A may be used to subtract out (or at leastminimize the adverse effects of) light source fluctuations. In oneembodiment, the output from an SC source 1801 may be collimated using aCaF₂ lens 1802 and then focused into the entrance slit of themonochromator 1803. At the exit slit, light at the selected wavelengthis collimated again and may be passed through a polarizer 1804 beforebeing incident on a calcium fluoride beam splitter 1805. After passingthrough the beam splitter 1805, the light is split into a sample 1806and reference 1807 arm to enable ratiometric detection that may cancelout effects of intensity fluctuations in the SC source 1801. The lightin the sample arm 1806 passes through the sample of interest and is thenfocused onto a HgCdTe detector 1808 connected to a pre-amp. A chopper1802 and lock-in amplifier 1810 setup enable low noise detection of thesample arm signal. The light in the reference arm 1807 passes through anempty container (cuvette, gas cell etc.) of the same kind as used in thesample arm. A substantially identical detector 1809, pre-amp and lock-inamplifier 1810 is used for detection of the reference arm signal. Thesignal may then be analyzed using a computer system 1811. This is oneparticular example of a method to remove fluctuations from the lightsource, but other components may be added and other configurations maybe used, and these are also intended to be covered by this disclosure.

Although particular examples of detection systems have been described,combinations of these systems or other systems may also be used, andthese are also within the scope of this disclosure. As one example,environmental fluctuations (such as turbulence or winds) may lead tofluctuations in the beam for active remote sensing or hyper-spectralimaging. A configuration such as FIG. 18A may be able to remove theeffect of environmental fluctuations. Yet another technique may be to“wobble” the light beam after the light source using a vibrating mirror.The motion may lead to the beam moving enough to wash out spatialfluctuations within the beam waist at the sample or detection system. Ifthe vibrating mirror is scanned faster than the integration time of thedetectors, then the spatial fluctuations in the beam may be integratedout. Alternately, some sort of synchronous detection system may be used,where the detection is synchronized to the vibrating frequency.

In addition to the problem of other blood constituents or analyteshaving overlapping spectral features, it may be difficult to observeglucose spectral signatures through the skin and its constituents ofwater, adipose, collagen and elastin. One approach to overcoming thisdifficulty may be to try to measure the blood constituents in veins thatare located at relatively shallow distances below the skin. Veins may bemore beneficial for the measurement than arteries, since arteries tendto be located at deeper levels below the skin. Also, in one embodimentit may be advantageous to use a differential measurement to subtract outsome of the interfering absorption lines from the skin. For example, aninstrument head may be designed to place one probe above a region ofskin over a blood vein, while a second probe may be placed at a regionof the skin without a noticeable blood vein below it. Then, bydifferencing the signals from the two probes, at least part of the skininterference may be cancelled out.

Two representative embodiments for performing such a differentialmeasurement are illustrated in FIG. 18B and FIG. 18C. In one embodimentshown in FIG. 18B, the dorsal of the hand 1820 may be used for measuringblood constituents or analytes. The dorsal of the hand 1820 may haveregions that have distinct veins 1821 as well as regions where the veinsare not as shallow or pronounced 1822. By stretching the hand andleaning it backwards, the veins 1821 may be accentuated in some cases. Anear-infrared diffuse reflectance measurement may be performed byplacing one probe 1823 above the vein-rich region 1821. To turn thisinto a differential measurement, a second probe 1824 may be placed abovea region without distinct veins 1822. Then, the outputs from the twoprobes may be subtracted 1825 to at least partially cancel out thefeatures from the skin. The subtraction may be done preferably in theelectrical domain, although it can also be performed in the opticaldomain or digitally/mathematically using sampled data based on theelectrical and/or optical signals. Although one example of using thedorsal of the hand 1820 is shown, many other parts of the hand can beused within the scope of this disclosure. For example, alternate methodsmay use transmission through the webbing between the thumb and thefingers 1826, or transmission or diffuse reflection through the tips ofthe fingers 1827.

In another embodiment, the dorsal of the foot 1830 may be used insteadof the hand. One advantage of such a configuration may be that forself-testing by a user, the foot may be easier to position theinstrument using both hands. One probe 1833 may be placed over regionswhere there are more distinct veins 1831, and a near-infrared diffusereflectance measurement may be made. For a differential measurement, asecond probe 1834 may be placed over a region with less prominent veins1832, and then the two probe signals may be subtracted, eitherelectronically or optically, or may be digitized/sampled and processedmathematically depending on the particular application andimplementation. As with the hand, the differential measurements may beintended to compensate for or subtract out (at least in part) theinterference from the skin. Since two regions are used in closeproximity on the same body part, this may also aid in removing somevariability in the skin from environmental effects such as temperature,humidity, or pressure. In addition, it may be advantageous to firsttreat the skin before the measurement, by perhaps wiping with a cloth ortreated cotton ball, applying some sort of cream, or placing an ice cubeor chilled bag over the region of interest.

Although two embodiments have been described, many other locations onthe body may be used using a single or differential probe within thescope of this disclosure. In yet another embodiment, the wrist may beadvantageously used, particularly where a pulse rate is typicallymonitored. Since the pulse may be easily felt on the wrist, there isunderlying the region a distinct blood flow. Other embodiments may useother parts of the body, such as the ear lobes, the tongue, the innerlip, the nails, the eye, or the teeth. Some of these embodiments will befurther described below. The ear lobes or the tip of the tongue may beadvantageous because they are thinner skin regions, thus permittingtransmission rather than diffuse reflection. However, the interferencefrom the skin is still a problem in these embodiments. Other regionssuch as the inner lip or the bottom of the tongue may be contemplatedbecause distinct veins are observable, but still the interference fromthe skin may be problematic in these embodiments. The eye may seem as aviable alternative because it is more transparent than skin. However,there are still issues with scattering in the eye. For example, theanterior chamber of the eye (the space between the cornea and the iris)comprises a fluid known as aqueous humor. However, the glucose level inthe eye chamber may have a significant temporal lag on changes in theglucose level compared to the blood glucose level.

As described in greater detail in commonly owned US Pat. App. Pub.2014/0188094, in some instances, it may be desirable to create multiplelocations of focused light. For example, the speed of the treatment forvaricose veins may be increased by causing thermal coagulation orocclusion at multiple locations. Multiple collimated or focused lightbeams may be created in one assembly. In such embodiments, optionally asurface cooling apparatus may be used, where a cooling fluid may beflowed either touching or in close proximity to the skin. Also, in thisparticular embodiment a cylindrical assembly may optionally be used,where the cylindrical length may be several millimeters in length anddefined by a clamp or mount placed on or near the leg. In oneembodiment, a window and/or lenslet array is also shown on thecylindrical surface for permitting the light to be incident on the skinand varicose vein at multiple spots. The lenslet array may comprisecircular, spherical or cylindrical lenses, depending on the type ofspots desired. As before, one advantage of placing the lenslet array inclose proximity to the skin and varicose vein may be that a high NA lensmay be used. Also, the input from the lens and/or mirror assembly to thelenslet array may be single large beam, or a plurality of smaller beams.In one embodiment, a plurality of spots may be created by the lensletarray to cause a plurality of locations of thermal coagulation in thevaricose vein. Any number of spots may be used and are intended to becovered by this disclosure.

In a non-limiting example, a plurality of spots may be used, or whatmight be called a fractionated beam. The fractionated laser beam may beadded to the laser delivery assembly or delivery head in a number ofways. In one embodiment, a screen-like spatial filter may be placed inthe pathway of the beam to be delivered to the biological tissue. Thescreen-like spatial filter can have opaque regions to block the lightand holes or transparent regions, through which the laser beam may passto the tissue sample. The ratio of opaque to transparent regions may bevaried, depending on the application of the laser. In anotherembodiment, a lenslet array can be used at or near the output interfacewhere the light emerges. In yet another embodiment, at least a part ofthe delivery fiber from the infrared laser system to the delivery headmay be a bundle of fibers, which may comprise a plurality of fiber coressurrounded by cladding regions. The fiber cores can then correspond tothe exposed regions, and the cladding areas can approximate the opaqueareas not to be exposed to the laser light. As an example, a bundle offibers may be excited by at least a part of the laser system output, andthen the fiber bundle can be fused together and perhaps pulled down to adesired diameter to expose to the tissue sample near the delivery head.In yet another embodiment, a photonic crystal fiber may be used tocreate the fractionated laser beam. In one non-limiting example, thephotonic crystal fiber can be coupled to at least a part of the lasersystem output at one end, and the other end can be coupled to thedelivery head. In a further example, the fractionated laser beam may begenerated by a heavily multi-mode fiber, where the speckle pattern atthe output may create the high intensity and low intensity spatialpattern at the output. Although several exemplary techniques areprovided for creating a fractionated laser beam, other techniques thatcan be compatible with optical fibers are also intended to be includedby this disclosure.

Although the output from a fiber laser may be from a single ormulti-mode fiber, different spatial spot sizes or spatial profiles maybe beneficial for different applications. For example, in some instancesit may be desirable to have a series of spots or a fractionated beamwith a grid of spots. In one embodiment, a bundle of fibers or a lightpipe with a plurality of guiding cores may be used. In anotherembodiment, one or more fiber cores may be followed by a lenslet arrayto create a plurality of collimated or focused beams. In yet anotherembodiment, a delivery light pipe may be followed by a grid-likestructure to divide up the beam into a plurality of spots. These arespecific examples of beam shaping, and other apparatuses and methods mayalso be used and are consistent with this disclosure.

Light Sources for SWIR and Near Infrared

There are a number of light sources that may be used in the nearinfrared. To be more specific, the discussion below will consider lightsources operating in the short wave infrared (SWIR), which may cover thewavelength range of approximately 1400 nm to 2500 nm. Other wavelengthranges may also be used for the applications described in thisdisclosure, so the discussion below is merely provided for exemplarytypes of light sources. The SWIR wavelength range may be valuable for anumber of reasons. The SWIR corresponds to a transmission window throughwater and the atmosphere. Also, the so-called “eye-safe” wavelengths arewavelengths longer than approximately 1400 nm as previously described.

Different light sources may be selected for the SWIR based on the needsof the application. Some of the features for selecting a particularlight source include power or intensity, wavelength range or bandwidth,spatial or temporal coherence, spatial beam quality for focusing ortransmission over long distance, and pulse width or pulse repetitionrate. Depending on the application, lamps, light emitting diodes (LEDs),laser diodes (LD's), tunable LD's, super-luminescent laser diodes(SLDs), fiber lasers or super-continuum sources (SC) may beadvantageously used. Also, different fibers may be used for transportingthe light, such as fused silica fibers, plastic fibers, mid-infraredfibers (e.g., tellurite, chalcogenides, fluorides, ZBLAN, etc), or ahybrid of these fibers.

Lamps may be used if low power or intensity of light is required in theSWIR, and if an incoherent beam is suitable. In one embodiment, in theSWIR an incandescent lamp that can be used is based on tungsten andhalogen, which have an emission wavelength between approximately 500 nmto 2500 nm. For low intensity applications, it may also be possible touse thermal sources, where the SWIR radiation is based on the black bodyradiation from the hot object. Although the thermal and lamp basedsources are broadband and have low intensity fluctuations, it may bedifficult to achieve a high signal-to-noise ratio due to the low powerlevels. Also, the lamp based sources tend to be energy inefficient.

In another embodiment, LED's can be used that have a higher power levelin the SWIR wavelength range. LED's also produce an incoherent beam, butthe power level can be higher than a lamp and with higher energyefficiency. Also, the LED output may more easily be modulated, and theLED provides the option of continuous wave or pulsed mode of operation.LED's are solid state components that emit a wavelength band that is ofmoderate width, typically between about 20 nm to 40 nm. There are alsoso-called super-luminescent LEDs that may even emit over a much widerwavelength range. In another embodiment, a wide band light source may beconstructed by combining different LEDs that emit in differentwavelength bands, some of which could preferably overlap in spectrum.One advantage of LEDs as well as other solid state components is thecompact size that they may be packaged into.

In yet another embodiment, various types of laser diodes may be used inthe SWIR wavelength range. Just as LEDs may be higher in power butnarrower in wavelength emission than lamps and thermal sources, the LDsmay be yet higher in power but yet narrower in wavelength emission thanLEDs. Different kinds of LDs may be used, including Fabry-Perot LDs,distributed feedback (DFB(LDs, distributed Bragg reflector (DBR) LDs.Since the LDs have relatively narrow wavelength range (typically under10 nm), in one embodiment a plurality of LDs may be used that are atdifferent wavelengths in the SWIR. The various LDs may be spatiallymultiplexed, polarization multiplexed, wavelength multiplexed, or acombination of these multiplexing methods. Also, the LDs may be fiberpig-tailed or have one or more lenses on the output to collimate orfocus the light. Another advantage of LDs is that they may be packagedcompactly and may have a spatially coherent beam output. Moreover,tunable LDs that can tune over a range of wavelengths are alsoavailable. The tuning may be done by varying the temperature, orelectrical current may be used in particular structures such asdistributed Bragg reflector LDs. In another embodiment, external cavityLDs may be used that have a tuning element, such as a fiber grating or abulk grating, in the external cavity.

In another embodiment, super-luminescent laser diodes may provide higherpower as well as broad bandwidth. An SLD is typically an edge emittingsemiconductor light source based on super-luminescence (e.g., this couldbe amplified spontaneous emission). SLDs combine the higher power andbrightness of LDs with the low coherence of conventional LEDs, and theemission band for SLD's may be 5 nm to 100 nm wide, preferably in the 60nm to 100 nm range. Although currently SLDs are commercially availablein the wavelength range of approximately 400 nm to 1700 nm, SLDs couldand may in the future be made that cover a broader region of the SWIR.

In yet another embodiment, high power LDs for either direct excitationor to pump fiber lasers and SC light sources may be constructed usingone or more laser diode bar stacks. FIG. 19 shows an example blockdiagram 1900 with building blocks for constructing the high power LDs.In this embodiment, one or more diode bar stacks 1901 may be used, wherethe diode bar stack may be an array of several single emitter LDs. Sincethe fast axis (e.g., vertical direction) may be nearly diffractionlimited while the slow-axis (e.g., horizontal axis) may be far fromdiffraction limited, different collimators 1902 may be used for the twoaxes.

The brightness may be increased by spatially combining the beams frommultiple stacks 1903. The combiner may include spatial interleaving,wavelength multiplexing, or a combination of the two. Different spatialinterleaving schemes may be used, such as using an array of prisms ormirrors with spacers to bend one array of beams into the beam path ofthe other. In another embodiment, segmented mirrors with alternatehigh-reflection and anti-reflection coatings may be used. Moreover, thebrightness may be increased by polarization beam combining 1904 the twoorthogonal polarizations, such as by using a polarization beam splitter.In a particular embodiment, the output may then be focused or coupledinto a large diameter core fiber. As an example, typical dimensions forthe large diameter core fiber range from diameters of approximately 100microns to 400 microns or more. Alternatively or in addition, a custombeam shaping module 1905 may be used, depending on the particularapplication. For example, the output of the high power LD may be useddirectly 1906, or it may be fiber coupled 1907 to combine, integrate, ortransport the high power LD energy. These high power LDs may grow inimportance because the LD powers can rapidly scale up. For example,instead of the power being limited by the power available from a singleemitter, the power may increase in multiples depending on the number ofdiodes multiplexed and the size of the large diameter fiber. AlthoughFIG. 19 is shown as one embodiment, some or all of the elements may beused in a high power LD, or additional elements may also be used.

SWIR Super-Continuum Lasers

Each of the light sources described above have particular strengths, butthey also may have limitations. For example, there is typically atrade-off between wavelength range and power output. Also, sources suchas lamps, thermal sources, and LEDs produce incoherent beams that may bedifficult to focus to a small area and may have difficulty propagatingfor long distances. An alternative source that may overcome some ofthese limitations is an SC light source. Some of the advantages of theSC source may include high power and intensity, wide bandwidth,spatially coherent beam that can propagate nearly transform limited overlong distances, and easy compatibility with fiber delivery.

Supercontinuum lasers may combine the broadband attributes of lamps withthe spatial coherence and high brightness of lasers. By exploiting amodulational instability initiated supercontinuum (SC) mechanism, anall-fiber-integrated SC laser with no moving parts may be built usingcommercial-off-the-shelf (COTS) components. Moreover, the fiber laserarchitecture may be a platform where SC in the visible,near-infrared/SWIR, or mid-IR can be generated by appropriate selectionof the amplifier technology and the SC generation fiber. But untilrecently, SC lasers were used primarily in laboratory settings sincetypically large, table-top, mode-locked lasers were used to pumpnonlinear media such as optical fibers to generate SC light. However,those large pump lasers may now be replaced with diode lasers and fiberamplifiers that gained maturity in the telecommunications industry.

In one embodiment, an all-fiber-integrated, high-powered SC light source2000 may be elegant for its simplicity (FIG. 20). The light may be firstgenerated from a seed laser diode 2001. For example, the seed LD 2001may be a distributed feedback (DFB) laser diode with a wavelength near1542 nm or 1550 nm, with approximately 0.5-2.0 ns pulsed output, andwith a pulse repetition rate between one kilohertz to about 100 MHz ormore. The output from the seed laser diode may then be amplified in amultiple-stage fiber amplifier 2002 comprising one or more gain fibersegments. In a particular embodiment, the first stage pre-amplifier 2003may be designed for optimal noise performance. For example, thepre-amplifier 2003 may be a standard erbium-doped fiber amplifier or anerbium/ytterbium doped cladding pumped fiber amplifier. Betweenamplifier stages 2003 and 2006, it may be advantageous to use band-passfilters 2004 to block amplified spontaneous emission and isolators 2005to prevent spurious reflections. Then, the power amplifier stage 2006may use a cladding-pumped fiber amplifier that may be optimized tominimize nonlinear distortion. The power amplifier fiber 2006 may alsobe an erbium-doped fiber amplifier, if only low or moderate power levelsare to be generated.

The SC generation 2007 may occur in the relatively short lengths offiber that follow the pump laser. Exemplary SC fiber lengths may rangefrom a few millimeters to 100 m or more. In one embodiment, the SCgeneration may occur in a first fiber 2008 where themodulational-instability initiated pulse break-up occurs primarily,followed by a second fiber 2009 where the SC generation and spectralbroadening occurs primarily.

In one embodiment, one or two meters of standard single-mode fiber (SMF)after the power amplifier stage may be followed by several meters of SCgeneration fiber. For this example, in the SMF the peak power may beseveral kilowatts and the pump light may fall in the anomalousgroup-velocity dispersion regime—often called the soliton regime. Forhigh peak powers in the anomalous dispersion regime, the nanosecondpulses may be unstable due to a phenomenon known as modulationalinstability, which is basically parametric amplification in which thefiber nonlinearity helps to phase match the pulses. As a consequence,the nanosecond pump pulses may be broken into many shorter pulses as themodulational instability tries to form soliton pulses from thequasi-continuous-wave background. Although the laser diode andamplification process starts with approximately nanosecond-long pulses,modulational instability in the short length of SMF fiber may formapproximately 0.5 ps to several-picosecond-long pulses with highintensity. Thus, the few meters of SMF fiber may result in an outputsimilar to that produced by mode-locked lasers, except in a much simplerand cost-effective manner.

The short pulses created through modulational instability may then becoupled into a nonlinear fiber for SC generation. The nonlinearmechanisms leading to broadband SC may include four-wave mixing orself-phase modulation along with the optical Raman effect. Since theRaman effect is self-phase-matched and shifts light to longerwavelengths by emission of optical photons, the SC may spread to longerwavelengths very efficiently. The short-wavelength edge may arise fromfour-wave mixing, and often times the short wavelength edge may belimited by increasing group-velocity dispersion in the fiber. In manyinstances, if the particular fiber used has sufficient peak power and SCfiber length, the SC generation process may fill the long-wavelengthedge up to the transmission window.

Mature fiber amplifiers for the power amplifier stage 2006 includeytterbium-doped fibers (near 1060 nm), erbium-doped fibers (near 1550nm), erbium/ytterbium-doped fibers (near 1550 nm), or thulium-dopedfibers (near 2000 nm). In various embodiments, candidates for SC fiber2009 include fused silica fibers (for generating SC between 0.8-2.7 μm),mid-IR fibers such as fluorides, chalcogenides, or tellurites (forgenerating SC out to 4.5 μm or longer), photonic crystal fibers (forgenerating SC between 0.4-1.7 μm), or combinations of these fibers.Therefore, by selecting the appropriate fiber-amplifier doping for 2006and nonlinear fiber 2009, SC may be generated in the visible,near-IR/SWIR, or mid-IR wavelength region.

The configuration 2000 of FIG. 20 is just one particular example, andother configurations can be used and are intended to be covered by thisdisclosure. For example, further gain stages may be used, and differenttypes of lossy elements or fiber taps may be used between the amplifierstages. In another embodiment, the SC generation may occur partially inthe amplifier fiber and in the pig-tails from the pump combiner or otherelements. In yet another embodiment, polarization maintaining fibers maybe used, and a polarizer may also be used to enhance the polarizationcontrast between amplifier stages. Also, not discussed in detail aremany accessories that may accompany this set-up, such as driverelectronics, pump laser diodes, safety shut-offs, and thermal managementand packaging.

In one embodiment, one example of the SC laser that operates in the SWIRis illustrated in FIG. 21. This SWIR SC source 2100 produces an outputof up to approximately 5 W over a spectral range of about 1.5-2.4microns, and this particular laser is made out of polarizationmaintaining components. The seed laser 2101 is a distributed feedback(DFB) laser operating near 1542 nm producing approximately 0.5 nsecpulses at an about 8 MHz repetition rate. The pre-amplifier 2102 isforward pumped and uses about 2 m length of erbium/ytterbium claddingpumped fiber 2103 (often also called dual-core fiber) with an inner corediameter of 12 microns and outer core diameter of 130 microns. Thepre-amplifier gain fiber 2103 is pumped using a 10 W laser diode near940 nm 2105 that is coupled in using a fiber combiner 2104.

In this particular 5 W unit, the mid-stage between amplifier stages 2102and 2106 comprises an isolator 2107, a band-pass filter 2108, apolarizer 2109 and a fiber tap 2110. The power amplifier 2106 uses anapproximately 4 m length of the 12/130 micron erbium/ytterbium dopedfiber 2111 that is counter-propagating pumped using one or more 30 Wlaser diodes near 940 nm 2112 coupled in through a combiner 2113. Anapproximately 1-2 m length of the combiner pig-tail helps to initiatethe SC process, and then a length of PM-1550 fiber 2115 (polarizationmaintaining, single-mode, fused silica fiber optimized for 1550 nm) isspliced 2114 to the combiner output.

If an output fiber of about 10 m in length is used, then the resultingoutput spectrum 2200 is shown in FIG. 22. The details of the outputspectrum 2200 depend on the peak power into the fiber, the fiber length,and properties of the fiber such as length and core size, as well as thezero dispersion wavelength and the dispersion properties. For example,if a shorter length of fiber is used, then the spectrum actually reachesto longer wavelengths (e.g., a 2 m length of SC fiber broadens thespectrum to about 2500 nm). Also, if extra-dry fibers are used with lessO—H content, then the wavelength edge may also reach to a longerwavelength. To generate more spectrum toward the shorter wavelengths,the pump wavelength (in this case around 1542 nm) should be close to thezero dispersion wavelength in the fiber. For example, by using adispersion shifted fiber or so-called non-zero dispersion shifted fiber,the short wavelength edge may shift to shorter wavelengths.

Although one particular example of a 5 W SWIR-SC has been described,different components, different fibers, and different configurations mayalso be used consistent with this disclosure. For instance, anotherembodiment of the similar configuration 2100 in FIG. 21 may be used togenerate high powered SC between approximately 1060 nm and 1800 nm. Forthis embodiment, the seed laser 2101 may be a distributed feedback laserdiode around 1064 nm, the pre-amplifier gain fiber 2103 may be aytterbium-doped fiber amplifier with 10/125 microns dimensions, and thepump laser 2105 may be a 10 W laser diode near 915 nm. A mode fieldadapter may be included in the mid-stage, in addition to the isolator2107, band pass filter 2108, polarizer 2109 and tap 2110. The gain fiber2111 in the power amplifier may be an about 20 m length ofytterbium-doped fiber with 25/400 microns dimension. The pump 2112 forthe power amplifier may be up to six pump diodes providing 30 W eachnear 915 nm. For this much pump power, the output power in the SC may beas high as 50 W or more.

In one embodiment, it may be desirous to generate high power SWIR SCover 1.4-1.8 microns and separately 2-2.5 microns (the window between1.8 and 2 microns may be less important due to the strong water andatmospheric absorption). For example, the SC source of FIG. 23A can leadto bandwidths ranging from about 1400 nm to 1800 nm or broader, whilethe SC source of FIG. 23B can lead to bandwidths ranging from about 1900nm to 2500 nm or broader. Since these wavelength ranges are shorter thanabout 2500 nm, the SC fiber can be based on fused silica fiber.Exemplary SC fibers include standard single-mode fiber SMF,high-nonlinearity fiber, high-NA fiber, dispersion shifted fiber,dispersion compensating fiber, and photonic crystal fibers.Non-fused-silica fibers can also be used for SC generation, includingchalcogenides, fluorides, ZBLAN, tellurites, and germanium oxide fibers.

In one embodiment, FIG. 23A illustrates an exemplary block diagram foran SC source 2300 capable of generating light between approximately 1400nm and 1800 nm or broader. As an example, a pump fiber laser similar toFIG. 21 can be used as the input to a SC fiber 2309. The seed laserdiode 2301 can comprise a DFB laser that generates, for example, severalmilliwatts of power around 1542 nm or 1553 nm. The fiber pre-amplifier2302 can comprise an erbium-doped fiber amplifier or an erbium/ytterbiumdoped double clad fiber. In this example a mid-stage amplifier 2303 canbe used, which can comprise an erbium/ytterbium doped double-clad fiber.A bandpass filter 2305 and isolator 2306 may be used between thepre-amplifier 2302 and mid-stage amplifier 2303. The power amplifierstage 2304 can comprise a larger core size erbium/ytterbium dopeddouble-clad fiber, and another bandpass filter 2307 and isolator 2308can be used before the power amplifier 2304. The output of the poweramplifier can be coupled to the SC fiber 2309 to generate the SC output2310. This is just one exemplary configuration for an SC source, andother configurations or elements may be used consistent with thisdisclosure.

In yet another embodiment, FIG. 23B illustrates a block diagram for anexemplary SC source 2350 capable of generating light betweenapproximately 1900 nm and 2500 nm or broader. As an example, the seedlaser diode 2351 can comprise a DFB or DBR laser that generates, forexample, several milliwatts of power around 1542 nm or 1553 nm. Thefiber pre-amplifier 2352 can comprise an erbium-doped fiber amplifier oran erbium/ytterbium doped double-clad fiber. In this example a mid-stageamplifier 2353 can be used, which can comprise an erbium/ytterbium dopeddouble-clad fiber. A bandpass filter 2355 and isolator 2356 may be usedbetween the pre-amplifier 2352 and mid-stage amplifier 2353. The poweramplifier stage 2354 can comprise a thulium doped double-clad fiber, andanother isolator 2357 can be used before the power amplifier 2354. Notethat the output of the mid-stage amplifier 2353 can be approximatelynear 1542 nm, while the thulium-doped fiber amplifier 2354 can amplifywavelengths longer than approximately 1900 nm and out to about 2100 nm.Therefore, for this configuration wavelength shifting may be requiredbetween 2353 and 2354. In one embodiment, the wavelength shifting can beaccomplished using a length of standard single-mode fiber 2358, whichcan have a length between approximately 5 m and 50 m, for example. Theoutput of the power amplifier 2354 can be coupled to the SC fiber 2359to generate the SC output 2360. This is just one exemplary configurationfor an SC source, and other configurations or elements can be usedconsistent with this disclosure. For example, the various amplifierstages can comprise different amplifier types, such as erbium dopedfibers, ytterbium doped fibers, erbium/ytterbium co-doped fibers andthulium doped fibers. One advantage of the SC lasers illustrated inFIGS. 20, 21, and 23A-B are that they may use all-fiber components, sothat the SC laser can be all-fiber, monolithically integrated with nomoving parts. The all-integrated configuration can consequently berobust and reliable.

FIGS. 20, 21 and 23A-B are examples of SC light sources that mayadvantageously be used for near-infrared or SWIR light generation invarious spectroscopy, active remote sensing and hyper-spectral imagingapplications. However, many other versions of the SC light sources mayalso be made that are intended to also be covered by this disclosure.For example, the SC generation fiber could be pumped by a mode-lockedlaser, a gain-switched semiconductor laser, an optically pumpedsemiconductor laser, a solid state laser, other fiber lasers, or acombination of these types of lasers. Also, rather than using a fiberfor SC generation, either a liquid or a gas cell might be used as thenonlinear medium in which the spectrum is to be broadened.

Even within the all-fiber versions illustrated such as in FIG. 21,different configurations could be used consistent with the disclosure.In one embodiment, it may be desirous to have a lower cost version ofthe SWIR SC laser of FIG. 21. One way to lower the cost could be to usea single stage of optical amplification, rather than two stages, whichmay be feasible if lower output power is required or the gain fiber isoptimized. For example, the pre-amplifier stage 2102 might be removed,along with at least some of the mid-stage elements. In yet anotherembodiment, the gain fiber could be double passed to emulate a two stageamplifier. In this example, the pre-amplifier stage 2102 might beremoved, and perhaps also some of the mid-stage elements. A mirror orfiber grating reflector could be placed after the power amplifier stage2106 that may preferentially reflect light near the wavelength of theseed laser 2101. If the mirror or fiber grating reflector can transmitthe pump light near 940 nm, then this could also be used instead of thepump combiner 2113 to bring in the pump light 2112. The SC fiber 2115could be placed between the seed laser 2101 and the power amplifierstage 2106 (SC is only generated after the second pass through theamplifier, since the power level may be sufficiently high at that time).In addition, an output coupler may be placed between the seed laserdiode 2101 and the SC fiber, which now may be in front of the poweramplifier 2106. In a particular embodiment, the output coupler could bea power coupler or divider, a dichroic coupler (e.g., passing seed laserwavelength but outputting the SC wavelengths), or a wavelength divisionmultiplexer coupler. This is just one further example, but a myriad ofother combinations of components and architectures could also be usedfor SC light sources to generate near-infrared or SWIR light that areintended to be covered by this disclosure.

FIG. 23C illustrates a reflection-spectroscopy based stand-off detectionsystem having an SC laser source. The set-up 2370 for thereflection-spectroscopy-based stand-off detection system includes an SCsource 2371. First, the diverging SC output is collimated to a 1 cmdiameter beam using a 25 mm focal length, 90 degrees off-axis, goldcoated, parabolic mirror 2372. To reduce the effects of chromaticaberration, refractive optics are avoided in the setup. All focusing andcollimation is done using metallic mirrors that have almost constantreflectivity and focal length over the entire SC output spectrum. Thesample 2374 is kept at a distance from the collimating mirror 2372,which provides a total round trip path length of twice the distancebefore reaching the collection optics 2375. A 12 cm diameter silvercoated concave mirror 2375 with a 75 cm focal length is kept 20 cm tothe side of the collimation mirror 2372. The mirror 2375 is used tocollect a fraction of the diffusely reflected light from the sample, andfocus it into the input slit of a monochromator 2376. Thus, the beam isincident normally on the sample 2374, but detected at a reflection angleof tan-1(0.2/5) or about 2.3 degrees. Appropriate long wavelength passfilters mounted in a motorized rotating filter wheel are placed in thebeam path before the input slit 2376 to avoid contribution from higherwavelength orders from the grating (300 grooves/mm, 2 μm blaze). Theoutput slit width is set to 2 mm corresponding to a spectral resolutionof 10.8 nm, and the light is detected by a 2 mmz×2 mm liquid nitrogencooled (77K) indium antimonide (InSb) detector 2377. The detected outputis amplified using a trans-impedance pre-amplifier 2377 with a gain ofabout 105 V/A and connected to a lock-in amplifier 2378 setup for highsensitivity detection. The chopper frequency is 400 Hz, and the lock-intime constant is set to 100 ms corresponding to a noise bandwidth ofabout 1 Hz. These are exemplary elements and parameter values, but otheror different optical elements may be used consistent with thisdisclosure.

By use of an active illuminator, a number of advantages may be achieved,such as higher signal-to-noise ratios. For example, one way to improvethe signal-to-noise ratio would be to use modulation and lock-intechniques. In one embodiment, the light source may be modulated, andthen the detection system would be synchronized with the light source.In a particular embodiment, the techniques from lock-in detection may beused, where narrow band filtering around the modulation frequency may beused to reject noise outside the modulation frequency. In an alternateembodiment, change detection schemes may be used, where the detectionsystem captures the signal with the light source on and with the lightsource off. Again, for this system the light source may be modulated.Then, the signal with and without the light source is differenced. Thismay enable the sun light changes to be subtracted out. In addition,change detection may help to identify objects that change in the fieldof view. Using a lock-in type technique (e.g., detecting at the samefrequency as the pulsed light source and also possibly phase locked tothe same signal), the detection system may be able to reject backgroundor spurious signals and increase the signal-to-noise ratio of themeasurement.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for spectroscopy, active remote sensing orhyper-spectral imaging. However, many other spectroscopy andidentification procedures can use the near-infrared or SWIR lightconsistent with this disclosure and are intended to be covered by thedisclosure. As one example, the fiber-based super-continuum lasers mayhave a pulsed output with pulse durations of approximately 0.5-2 nsecand pulse repetition rates of several Megahertz. Therefore, thenear-infrared or SWIR spectroscopy, active remote sensing orhyper-spectral imaging applications may also be combined with LIDAR-typeapplications. Namely, the distance or time axis can be added to theinformation based on time-of-flight measurements. For this type ofinformation to be used, the detection system would also have to betime-gated to be able to measure the time difference between the pulsessent and the pulses received. By calculating the round-trip time for thesignal, the distance of the object may be judged. In another embodiment,GPS (global positioning system) information may be added, so thenear-infrared or SWIR spectroscopy, active remote sensing orhyper-spectral imagery would also have a location tag on the data.Moreover, the near-infrared or SWIR spectroscopy, active remote sensingor hyper-spectral imaging information could also be combined withtwo-dimensional or three-dimensional images to provide a physicalpicture as well as a chemical composition identification of thematerials. These are just some modifications of the near-infrared orSWIR spectroscopy, active remote sensing or hyper-spectral imagingsystem described in this disclosure, but other techniques may also beadded or combinations of these techniques may be added, and these arealso intended to be covered by this disclosure.

Wireless Link to the Cloud

The non-invasive blood constituent or analytes measurement device mayalso benefit from communicating the data output to the “cloud” (e.g.,data servers and processors in the web remotely connected) via wiredand/or wireless communication strategies. The non-invasive devices maybe part of a series of biosensors applied to the patient, andcollectively these devices form what might be called a body area networkor a personal area network. The biosensors and non-invasive devices maycommunicate to a smart phone, tablet, personal data assistant, computer,and/or other microprocessor-based device, which may in turn wirelesslyor over wire and/or fiber optically transmit some or all of the signalor processed data to the internet or cloud. The cloud or internet may inturn send the data to doctors or health care providers as well as thepatients themselves. Thus, it may be possible to have a panoramic,high-definition, relatively comprehensive view of a patient that doctorscan use to assess and manage disease, and that patients can use to helpmaintain their health and direct their own care.

In a particular embodiment 2400 illustrated in FIG. 24, thephysiological measurement device or non-invasive blood constituentmeasurement device 2401 may comprise a transmitter 2403 to communicateover a first communication link 2404 in the body area network orpersonal area network to a receiver in a smart phone, tablet cell phone,PDA, or computer 2405. For the measurement device 2401, it may also beadvantageous to have a processor 2402 to process some of thephysiological data, since with processing the amount of data to transmitmay be less (hence, more energy efficient). The first communication link2404 may operate through the use of one of many wireless technologiessuch as Bluetooth, Zigbee, WiFi, IrDA (infrared data association),wireless USB, or Z-wave, to name a few. Alternatively, the communicationlink 2404 may occur in the wireless medical band between 2360 and 2390MHz, which the FCC allocated for medical body area network devices, orin other designated medical device or WMTS bands. These are examples ofdevices that can be used in the body area network and surroundings, butother devices could also be used and are included in the scope of thisdisclosure.

The personal device 2405 may store, process, display, and transmit someof the data from the measurement device 2401. The device 2405 maycomprise a receiver, transmitter, display, voice control and speakers,and one or more control buttons or knobs and a touch screen. Examples ofthe device 2405 include smart phones such as the Apple iPhones® orphones operating on the Android or Microsoft systems. In one embodiment,the device 2405 may have an application, software program, or firmwareto receive and process the data from the measurement device 2401. Thedevice 2405 may then transmit some or all of the data or the processeddata over a second communication link 2406 to the internet or “cloud”2407. The second communication link 2406 may advantageously comprise atleast one segment of a wireless transmission link, which may operateusing WiFi or the cellular network. The second communication link 2406may additionally comprise lengths of fiber optic and/or communicationover copper wires or cables.

The internet or cloud 2407 may add value to the measurement device 2401by providing services that augment the physiological data collected. Ina particular embodiment, some of the functions performed by the cloudinclude: (a) receive at least a fraction of the data from the device2405; (b) buffer or store the data received; (c) process the data usingsoftware stored on the cloud; (d) store the resulting processed data;and (e) transmit some or all of the data either upon request or based onan alarm. As an example, the data or processed data may be transmitted2408 back to the originator (e.g., patient or user), it may betransmitted 2409 to a health care provider or doctor, or it may betransmitted 2410 to other designated recipients.

The cloud 2407 may provide a number of value-add services. For example,the cloud application may store and process the physiological data forfuture reference or during a visit with the healthcare provider. If apatient has some sort of medical mishap or emergency, the physician canobtain the history of the physiological parameters over a specifiedperiod of time. In another embodiment, if the physiological parametersfall out of acceptable range, alarms may be delivered to the user 2408,the healthcare provider 2409, or other designated recipients 2410. Theseare just some of the features that may be offered, but many others maybe possible and are intended to be covered by this disclosure. As anexample, the device 2405 may also have a GPS sensor, so the cloud 2407may be able to provide time, data and position along with thephysiological parameters. Thus, if there is a medical emergency, thecloud 2407 could provide the location of the patient to the healthcareprovider 2409 or other designated recipients 2410. Moreover, thedigitized data in the cloud 2407 may help to move toward what is oftencalled “personalized medicine.” Based on the physiological parameterdata history, medication or medical therapies may be prescribed that arecustomized to the particular patient.

Beyond the above benefits, the cloud application 2407 and application onthe device 2405 may also have financial value for companies developingmeasurement devices 2401 such as a non-invasive blood constituentmonitor. In the case of glucose monitors, the companies make themajority of their revenue on the measurement strips. However, with anon-invasive monitor, there is no need for strips, so there is less ofan opportunity for recurring costs (e.g., the razor/razor blade modeldoes not work for non-invasive devices). On the other hand, people maybe willing to pay a periodic fee for the value-add services provided onthe cloud 2407. Diabetic patients, for example, would probably bewilling to pay a periodic fee for monitoring their glucose levels,storing the history of the glucose levels, and having alarm warningswhen the glucose level falls out of range. Similarly, patients takingketone bodies supplement for treatment of disorders characterized byimpaired glucose metabolism (e.g., Alzheimer's, Parkinson's,Huntington's or ALS) may need to monitor their ketone bodies level.These patients would also probably be willing to pay a periodic fee forthe value-add services provided on the cloud 2407. Thus, by leveragingthe advances in wireless connectivity and the widespread use of handhelddevices such as smart phones that can wirelessly connect to the cloud,businesses can build a recurring cost business model even usingnon-invasive measurement devices.

Described herein are just some examples of the beneficial use ofnear-infrared or SWIR lasers for non-invasive monitoring of glucose,ketones, HbA1c and other blood constituents. However, many other medicalprocedures can use the near-infrared or SWIR light consistent with thisdisclosure and are intended to be covered by the disclosure.

Although the present disclosure has been described in severalembodiments, a myriad of changes, variations, alterations,transformations, and modifications may be suggested to one skilled inthe art, and it is intended that the present disclosure encompass suchchanges, variations, alterations, transformations, and modifications asfalling within the spirit and scope of the appended claims.

While exemplary embodiments are described above, it is not intended thatthese embodiments describe all possible forms of the disclosure. Rather,the words used in the specification are words of description rather thanlimitation, and it is understood that various changes may be madewithout departing from the spirit and scope of the disclosure.Additionally, the features of various implementing embodiments may becombined to form further embodiments of the disclosure. While variousembodiments may have been described as providing advantages or beingpreferred over other embodiments with respect to one or more desiredcharacteristics, as one skilled in the art is aware, one or morecharacteristics may be compromised to achieve desired system attributes,which depend on the specific application and implementation. Theseattributes include, but are not limited to: cost, strength, durability,life cycle cost, marketability, appearance, packaging, size,serviceability, weight, manufacturability, ease of assembly, etc. Theembodiments described herein that are described as less desirable thanother embodiments or prior art implementations with respect to one ormore characteristics are not outside the scope of the disclosure and maybe desirable for particular applications.

What is claimed is:
 1. A smart phone or tablet, comprising: a first partcomprising a first at least one of a plurality of laser diodes, thefirst at least one of the plurality of laser diodes configured to bepulsed; a second part comprising a second at least one of the pluralityof laser diodes; the plurality of laser diodes configured to generatelight having one or more optical wavelengths, wherein at least a portionof the one or more optical wavelengths is a near-infrared wavelengthbetween 700 nanometers and 2500 nanometers, and wherein at least aportion of the plurality of laser diodes comprises one or moredistributed Bragg reflectors; at least a portion of light from theplurality of laser diodes directed to tissue comprising skin; an arrayof laser diodes configured to generate light having one or more opticalwavelengths, wherein at least a portion of the one or more opticalwavelengths is a near-infrared wavelength between 700 nanometers and2500 nanometers, and wherein at least a portion of the array of laserdiodes comprises one or more distributed Bragg reflectors; an assemblyin front of the array of laser diodes configured to receive at least aportion of the light from the array of laser diodes, the array of laserdiodes and the assembly configured to form the light into a plurality ofspots and to direct at least some of the spots to the tissue; a firstreceiver comprising one or more detectors; the first receiver configuredto receive at least a portion of light reflected from the tissue fromthe first at least one of the plurality of laser diodes, wherein thefirst receiver is configured to perform a time-of-flight measurement bymeasuring a time difference between the generated light from the firstat least one of the plurality of laser diodes and light reflected fromthe tissue from the first at least one of the plurality of laser diodes;an infrared camera configured to receive at least a portion of the lightfrom the second at least one of the plurality of laser diodes reflectedfrom the tissue, wherein the infrared camera generates data based atleast in part on the received light; wherein the smart phone or tabletis configured to receive and process at least a portion of thetime-of-flight measurement, and to generate a two-dimensional orthree-dimensional image using at least part of the data from theinfrared camera, and wherein the two-dimensional or three-dimensionalimage is used in part to identify one or more features corresponding tothe skin; and the smart phone or tablet further comprising a wirelessreceiver, a wireless transmitter, a display, a voice input module, and aspeaker.
 2. The smart phone or tablet of claim 1, wherein the infraredcamera is further configured to: generate a first signal in response tolight received while the plurality of laser diodes and the array oflaser diodes are off; and generate a second signal in response to lightreceived while at least one of the plurality of laser diodes or at leastone laser diode of the array of laser diodes is on, the received lightincluding at least some light from the at least one of the plurality oflaser diodes reflected from the tissue or at least some light from thearray of laser diodes reflected from the tissue; wherein the smart phoneor tablet is further configured to use a difference between the firstsignal and the second signal to, at least in part, generate thetwo-dimensional or three-dimensional image.
 3. The smart phone or tabletof claim 1, wherein the first receiver further comprises one or morefilters in front of the one or more detectors to select a fraction ofthe one or more optical wavelengths.
 4. The smart phone or tablet ofclaim 1, wherein the second at least one of the plurality of laserdiodes is also configured to be pulsed, and wherein the infrared camerais configured to be synchronized to the second at least one of theplurality of laser diodes.
 5. The smart phone or tablet of claim 1,wherein the second at least one of the plurality of laser diodes has amodulation frequency, and wherein the infrared camera is configured touse a lock-in technique that detects the modulation frequency.
 6. Thesmart phone or tablet of claim 5, wherein the modulation frequency has aphase, and wherein the infrared camera is configured to lock onto thephase.
 7. A smart phone or tablet, comprising: a first part comprising afirst at least one of a plurality of laser diodes, the first at leastone of the plurality of laser diodes configured to be pulsed; a secondpart comprising a second at least one of the plurality of laser diodes;the plurality of laser diodes configured to generate light having one ormore optical wavelengths, wherein at least a portion of the one or moreoptical wavelengths is a near-infrared wavelength between 700 nanometersand 2500 nanometers, and wherein at least a portion of the plurality oflaser diodes comprises one or more distributed Bragg reflectors; atleast a portion of light from the plurality of laser diodes directed totissue comprising skin; an array of laser diodes configured to generatelight having one or more optical wavelengths, wherein at least a portionof the one or more optical wavelengths is a near-infrared wavelengthbetween 700 nanometers and 2500 nanometers, and wherein at least aportion of the array of laser diodes comprises one or more distributedBragg reflectors; an assembly in front of the array of laser diodesconfigured to receive at least a portion of the light from the array oflaser diodes, the array of laser diodes and the assembly configured toform the light into a plurality of spots and to direct at least some ofthe spots to the tissue; a first receiver comprising one or moredetectors; the first receiver configured to receive at least a portionof light reflected from the tissue from the first at least one of theplurality of laser diodes; an infrared camera configured to receive atleast a portion of the light from the second at least one of theplurality of laser diodes reflected from the tissue, wherein theinfrared camera generates data based at least in part on the receivedlight; wherein the smart phone or tablet is configured to generate atwo-dimensional or three-dimensional image using at least part of thedata from the infrared camera; and the smart phone or tablet furthercomprising a wireless receiver, a wireless transmitter, a display, avoice input module, and a speaker.
 8. The smart phone or tablet of claim7, wherein the first receiver is configured to perform a time-of-flightmeasurement by measuring a time difference between the generated lightfrom the first at least one of the plurality of laser diodes and lightreflected from the tissue from the first at least one of the pluralityof laser diodes, and wherein the smart phone or tablet is configured toreceive and process at least a portion of the time-of-flightmeasurement.
 9. The smart phone or tablet of claim 8, wherein the secondat least one of the plurality of laser diodes is also configured to bepulsed, and wherein the infrared camera is configured to be synchronizedto the second at least one of the plurality of laser diodes.
 10. Thesmart phone or tablet of claim 9, wherein the first receiver furthercomprises one or more filters in front of the one or more detectors toselect a fraction of the one or more optical wavelengths.
 11. The smartphone or tablet of claim 10, wherein the infrared camera is furtherconfigured to: generate a first signal in response to light receivedwhile the plurality of laser diodes and the array of laser diodes areoff; and generate a second signal in response to light received while atleast one of the plurality of laser diodes or at least one laser diodeof the array of laser diodes is on, the received light including atleast some light from the at least one of the plurality of laser diodesreflected from the tissue or at least some light from the array of laserdiodes reflected from the tissue; wherein the smart phone or tablet isfurther configured to use a difference between the first signal and thesecond signal to, at least in part, generate the two-dimensional orthree-dimensional image.
 12. The smart phone or tablet of claim 11,wherein the second at least one of the plurality of laser diodes has amodulation frequency, and wherein the infrared camera is configured touse a lock-in technique that detects the modulation frequency.
 13. Thesmart phone or tablet of claim 12, wherein the modulation frequency hasa phase, and wherein the infrared camera is configured to lock onto thephase.
 14. The smart phone or tablet of claim 13, wherein thetwo-dimensional or three-dimensional image is used in part to identifyone or more features corresponding to the skin.
 15. A smart phone ortablet, comprising: a first part comprising a first at least one of aplurality of laser diodes, the first at least one of the plurality oflaser diodes configured to be pulsed; a second part comprising a secondat least one of the plurality of laser diodes, the second at least oneof the plurality of laser diodes also configured to be pulsed; theplurality of laser diodes configured to generate light having one ormore optical wavelengths, wherein at least a portion of the one or moreoptical wavelengths is a near-infrared wavelength between 700 nanometersand 2500 nanometers, and wherein at least a portion of the plurality oflaser diodes comprises one or more distributed Bragg reflectors; atleast a portion of light from the plurality of laser diodes directed totissue comprising skin; an array of laser diodes configured to generatelight having one or more optical wavelengths, wherein at least a portionof the one or more optical wavelengths is a near-infrared wavelengthbetween 700 nanometers and 2500 nanometers, and wherein at least aportion of the array of laser diodes comprises one or more distributedBragg reflectors; an assembly in front of the array of laser diodesconfigured to receive at least a portion of the light from the array oflaser diodes, the array of laser diodes and the assembly configured toform the light into a plurality of spots and to direct at least some ofthe spots to the tissue; a first receiver comprising one or moredetectors; the first receiver configured to receive at least a portionof light reflected from the tissue from the first at least one of theplurality of laser diodes, wherein the first receiver is configured toperform a time-of-flight measurement by measuring a time differencebetween the generated light from the first at least one of the pluralityof laser diodes and light reflected from the tissue from the first atleast one of the plurality of laser diodes, and wherein the firstreceiver further comprises one or more filters in front of the one ormore detectors to select a fraction of the one or more opticalwavelengths; an infrared camera configured to receive at least a portionof the light from the second at least one of the plurality of laserdiodes reflected from the tissue, wherein the infrared camera generatesdata based at least in part on the received light; wherein the smartphone or tablet is configured to receive and process at least a portionof the time-of-flight measurement, and to generate a two-dimensional orthree-dimensional image using at least part of the data from theinfrared camera.
 16. The smart phone or tablet of claim 15, wherein theinfrared camera is configured to be synchronized to the second at leastone of the plurality of laser diodes.
 17. The smart phone or tablet ofclaim 16, wherein the second at least one of the plurality of laserdiodes has a modulation frequency, and wherein the infrared camera isconfigured to use a lock-in technique that detects the modulationfrequency.
 18. The smart phone or tablet of claim 17, wherein themodulation frequency has a phase, and wherein the infrared camera isconfigured to lock onto the phase.
 19. The smart phone or tablet ofclaim 18, wherein the infrared camera is further configured to: generatea first signal in response to light received while the plurality oflaser diodes and the array of laser diodes are off; and generate asecond signal in response to light received while at least one of theplurality of laser diodes or at least one laser diode of the array oflaser diodes is on, the received light including at least some lightfrom the at least one of the plurality of laser diodes reflected fromthe tissue or at least some light from the array of laser diodesreflected from the tissue; wherein the smart phone or tablet is furtherconfigured to use a difference between the first signal and the secondsignal to, at least in part, generate the two-dimensional orthree-dimensional image.
 20. The smart phone or tablet of claim 19,wherein the two-dimensional or three-dimensional image is used in partto identify one or more features corresponding to the skin.